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Retrospective, longitudinal analysis of sham observed eyes from the phase 3 OAKS and DERBY trials evaluated the relationship between geographic atrophy (GA) growth and the presence or absence of outer retinal tubulation (ORT).
Methods
Prevalence rates of ORT were calculated, and analysis of GA growth was performed using fundus autofluorescence and optical coherence tomography (OCT).
Results
ORT prevalence rates were 32%, 37.5%, and 43% at baseline, month 12, and month 24, respectively. Eyes with a fully formed ORT at baseline had 23.6% less GA area growth over 24 months compared with GA without ORT present at baseline.
Conclusion
The presence of ORT at baseline on OCT may be reflective of slower growth of GA, irrespective of GA location, as was noted in this series. The potential diagnostic impact of ORT should be considered when designing clinical studies for GA and when analyzing the results of such studies.
Trial registration
OAKS: ClinicalTrials.gov identifier NCT03525613 (registered May 15, 2018); EudraCT identifier 2018-001435-52 (registered September 27, 2018). DERBY: ClinicalTrials.gov identifier NCT03525600 (registered May 15, 2018); EudraCT identifier 2018-001436-22 (registered September 21, 2018).
Previous Presentation: Presented in part at the 2024 Association for Research in Vision and Ophthalmology Annual Meeting and at the 2024 American Society of Retina Specialists Annual Meeting.
Key Summary Points
Why carry out this study?
Outer retinal tubulation (ORT) is an optical coherence tomography finding that may be present in eyes with advanced age-related macular degeneration.
This retrospective, longitudinal analysis evaluated the relationship between the presence or absence of ORT and growth of geographic atrophy (GA) within sham observed eyes from the large phase 3 OAKS and DERBY clinical trials.
What was learned from the study?
Eyes with a fully formed ORT at baseline had 23.6% slower GA area growth over 24 months compared with GA growth in eyes without ORT present at baseline.
The presence of ORT may be relevant for clinical trial design, risk stratification, and management in patients with GA.
Introduction
Outer retinal tubulation (ORT) is an optical coherence tomography (OCT) finding associated with advanced retinal degenerative disease [1]. ORT is characterized by formation of tubular structures within the degenerating outer nuclear layer and a round or oval hyporeflective core containing photoreceptors, retinal pigment epithelium (RPE), and Müller cells, surrounded by a hyperreflective band representing the external limiting membrane (ELM) [2]. ORT was initially characterized by Zweifel et al. in 2009 [3]. Although the exact pathophysiology of ORT is not fully understood, the reorganization of cells appears to be prompted by injury to photoreceptors and RPE cells [1, 3]. Moreover, Müller cells may play a key role in the ORT formation process [2]. It has been hypothesized that ORT arises as a consequence of RPE atrophy, accompanied by descent of the ELM, which transitions from a flat to a curved configuration before eventually folding into a scrolled shape [2]. In response to loss of retinal tissue, degenerating photoreceptor cells undergo structural rearrangement, forming ORT as an adaptive mechanism [3]. Schaal et al. described four histological subtypes of photoreceptor degeneration based on the contents within the luminal walls of ORT: nascent (containing photoreceptor outer segments [OS] and inner segments [IS]), mature (IS only), degenerate (degenerating or no IS), and end stage (containing no recognizable photoreceptors, only Müller cells forming ELM). ORT may also exist in either a closed or open configuration [4].
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ORT is most commonly found in eyes with advanced age-related macular degeneration (AMD) but is also observed in late stages of a number of other retinal disorders, including Stargardt disease, Best disease, retinitis pigmentosa, and choroideremia [1, 5, 6]. In the context of late AMD, ORT can be imaged in eyes with either geographic atrophy (GA) or exudative macular neovascularization (MNV) [1]. Previous studies have considered the potential clinical implications of ORT, reporting a poorer visual acuity outcome in neovascular AMD eyes with ORT [7], while there have been mixed findings regarding the association of ORT with GA area growth rates [8, 9]. Post hoc analyses of sham observed eyes from FILLY (NCT02503332), a phase 2 study evaluating pegcetacoplan-induced C3/C3b inhibition treatment for GA due to AMD [10], and the combined OAKS (NCT03525613) and DERBY (NCT03525600) phase 3 clinical trials, found a slower mean GA growth rate and lower loss of visual acuity in sham eyes with ORT present at baseline [11, 12].
This analysis evaluated the relationship between ORT and GA growth rates within sham observed eyes from the large OAKS and DERBY trials, which ultimately led to the approval of pegcetacoplan in the USA as the first treatment for GA secondary to AMD.
Methods
This retrospective, longitudinal analysis included eyes randomized to the sham observed group from the 24-month phase 3 OAKS (NCT03525613) and DERBY (NCT03525600) trials [13]. For inclusion in this analysis, baseline OCT utilizing the Spectralis (Heidelberg Engineering, Heidelberg, Germany) and at least one post-baseline GA area measurement via fundus autofluorescence (FAF) were required. Two independent graders (KH, BS) evaluated all included eye OCT images at baseline, month 12, and month 24 for the presence or absence (dichotomic factor) of a fully formed ORT (Fig. 1a, b), with any discrepancies arbitrated by a third reader (SS). OCTs were evaluated by reviewing each of the 49 horizontal raster scans per eye for the presence of a fully formed ORT, which was defined as a hyperreflective circular border completely surrounding a hyporeflective core and located in the outer nuclear layer. Independent reading center (Digital Angiography Reading Center, Great Neck, NY, USA) evaluation using OCT and FAF classified GA location as either subfoveal or nonsubfoveal based on the distance from the atrophy border to the center point of the fovea, with a distance of ≥ 1 µm defining nonsubfoveal GA. The change in GA area was based on baseline ORT status and was assessed as the square root of the total GA area (millimeters) as measured by FAF over 24 months. GA measurements were graded by the same reading center and utilized independent manual measurements of GA features; mean area was determined by two masked readers, while the median area was determined by three readers. Within-group t tests were performed to compare changes from baseline in square root of total GA area at months 12 and 24 between eyes with ORT versus eyes without ORT at baseline.
Fig. 1
ORT (white arrow) on cross sectional OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) of a sham eye in the OAKS and DERBY trials (a) and magnified view of the region with ORT (b). Round hyporeflective core completely surrounded by a hyperreflective border and located in the region of GA. Note the choroidal hypertransmission and complete loss of the photoreceptor and RPE layers, consistent with advanced subfoveal GA. GA geographic atrophy, OCT optical coherence tomography, ORT outer retinal tubulation, RPE retinal pigment epithelium
As this was a retrospective analysis, institutional review board approval was not required. For the OAKS and DERBY studies, study protocols were approved by institutional review boards or ethics committees at each site. Both studies adhered to the Declaration of Helsinki. All patients who participated in the OAKS and DERBY studies provided written informed consent.
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Results
A total of 300 sham observed eyes (158 from OAKS, 142 from DERBY) met the imaging criteria and were included in this 24-month analysis. Baseline characteristics (Table 1) were consistent with the typical profile of patients with GA secondary to AMD and allowed the assessment of the prevalence and association of ORT without the confounding factor of previous exudative AMD. In the modified intention-to-treat population (N = 305), the discontinuation rate was higher among patients without ORT at baseline (10.5% [32/305]) than in patients with ORT at baseline (3.3% [10/305]). Overall, eight patients discontinued because of death, all without ORT at baseline.
Table 1
Baseline characteristics of included sham control eyes
Parameters
Overall
(N = 300)
ORT present
(n = 96)
ORT absent
(n = 204)
Age, mean (SD), years
78.1 (7.0)
75.3 (7.1)
79.4 (6.6)
Female, %
63.7
62.5
64.2
Caucasian, %
93.0
94.8
92.2
Area of GA, mean (SD), mm2
8.0 (4.0)
8.3 (3.9)
7.9 (4.0)
Unifocal GA, %
33.3
31.3
34.3
Bilateral GA, %
78.0
79.2
77.5
BCVA ETDRS letter score, mean (SD)
58.7 (16.5)
58.7 (16.0)
58.7 (16.7)
BCVA best-corrected visual acuity, ETDRS Early Treatment of Diabetic Retinopathy Study, GA geographic atrophy, ORT outer retinal tubulation, SD standard deviation
ORT prevalence rates were 32% (96/300) at baseline, 37.5% (106/283) at month 12, and 43% (114/265) at month 24. At study baseline, subfoveal GA was present in 66.7% (200/300) of eyes and ORT was present in 37.5% (75/200) of these eyes. Nonsubfoveal GA was present in 33.3% (100/300) of eyes; ORT was present in 21% (21/100) of these eyes. Mean square root of total GA growth in eyes with a fully formed ORT at baseline was on average 23.6% slower over 24 months compared with GA growth in eyes without ORT present at baseline (P < 0.001; Table 2 and Fig. 2a).
Table 2
Change in square root of total GA area at month 12 and month 24 by GA location and baseline ORT status
Combined subfoveal & nonsubfoveal
Subfoveal
Nonsubfoveal
ORT present
ORT absent
ORT present
ORT absent
ORT present
ORT absent
Month 12
Change from baseline in square root of total GA area, mean
(95% CI), mm
0.25
(0.22, 0.28)
0.36
(0.33, 0.39)
0.23
(0.20, 0.26)
0.30
(0.27, 0.33)
0.31
(0.24, 0.39)
0.45
(0.39, 0.50)
Change from baseline in square root of total GA area, mean
(95% CI), %
9.06
(7.89, 10.23)
13.93
(12.66, 15.19)
8.50
(7.23, 9.77)
11.85
(10.50, 13.20)
11.26
(8.30, 14.30)
17.14
(14.86, 19.42)
P value (ORT vs no ORT)
< 0.0001
0.0012
0.0179
Month 24
Change from baseline in square root of total GA area, mean
(95% CI), mm
0.53
(0.47, 0.58)
0.69
(0.64, 0.74)
0.50
(0.44, 0.56)
0.59
(0.54, 0.63)
0.64
(0.51, 0.77)
0.86
(0.77, 0.95)
Change from baseline in square root of total GA area, mean
(95% CI), %
19.14
(16.98, 21.30)
27.20
(24.97, 29.43)
18.15
(15.84, 20.46)
23.29
(20.97, 25.61)
23.29
(17.51, 29.07)
33.76
(29.64, 37.88)
P value (ORT vs no ORT)
< 0.0001
0.0236
0.0225
GA location was subfoveal, nonsubfoveal, or combined subfoveal and nonsubfoveal. Baseline ORT status was absent or present
CI confidence interval, GA geographic atrophy, ORT outer retinal tubulation
Fig. 2
Change in square root of total GA area over time by baseline ORT status in patients with combined subfoveal and nonsubfoveal GA (a), subfoveal GA (b), and nonsubfoveal GA (c)
Consistent with the overall population analysis, the presence of ORT at baseline was associated with significantly slower mean GA area growth at 24 months in both the subfoveal and nonsubfoveal GA subgroups (Table 2 and Figs. 2b, c). In eyes with ORT at baseline, enlargement of the subfoveal GA area was 14.9% slower and enlargement of the nonsubfoveal GA area was 25.4% slower over 24 months than in eyes without ORT present at baseline (subfoveal, P = 0.0236; nonsubfoveal, P = 0.0225).
Discussion
GA is a heterogeneous clinical finding characterized by chronic, progressive, and irreversible loss and damage to the outer retina, specifically affecting the photoreceptors, RPE, Bruch’s membrane, and choriocapillaris [14, 15]. In patients with GA due to AMD, various clinical, genetic, and anatomical factors have been proposed to influence the rate of disease progression and overall severity. Some of these factors include smoking status, family history, severity of AMD in the fellow eye, and GA focality, location, and size [16, 17].
This retrospective study presents the largest natural history dataset evaluating the relationship between ORT and GA area growth, one of several imaging biomarkers that has been investigated for its potential role in assessing GA disease severity and progression in late-stage AMD [18]. Consistent with post hoc findings from other GA studies, including the phase 2 FILLY and MAHALO (NCT01229215) trials [8, 11], slower GA growth rates were observed in sham-treated eyes with ORT in the OAKS and DERBY studies. This finding has potential clinical implications for trial design, risk stratification, and disease management in patients with AMD. Disease characteristics previously associated with increased risk of GA progression include bilaterality, multifocality, nonsubfoveal location, and the presence of 20 or fewer drusen groups [19‐23]. Along with these known risk factors, consideration of ORT status may have a role in optimizing clinical outcomes in the real-world setting. The potentially confounding impact of ORT on risk assessment and disease management warrants further investigation.
In our analysis, ORT was detected in eyes with both subfoveal and nonsubfoveal GA but was more frequently observed in subfoveal GA at baseline. This contrasts with findings from the FILLY trial, where ORT prevalence was more similar between subfoveal and nonsubfoveal GA at 26% and 22%, respectively. The study discontinuation rate was higher among patients without ORT at baseline (10.5%) than in patients with ORT at baseline (3.3%), suggesting that there is no bias toward patient dropout with more advanced disease. Additionally, in both subgroups, ORT prevalence increased over the 24-month follow-up period, suggesting a higher likelihood of ORT development with advancing AMD.
This analysis is limited by its post hoc design and the consideration of only a single factor, without accounting for other potential contributors, including systemic, genetic, clinical, and imaging findings that may influence GA growth.
Conclusion
The presence of ORT at baseline on OCT may be a factor indicative of slower GA progression, regardless of GA location, as observed in this series. The potential diagnostic significance of ORT should be considered when designing clinical studies on GA and interpreting their results.
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Acknowledgements
Medical Writing, Editorial, and Other Assistance
Professional medical writing and editorial support was provided by Braden Roth, PhD (OPEN Health Communications), and funded by Apellis Pharmaceuticals.
Declarations
Conflict of Interest
Srinivas Sadda has received consulting fees from Apellis, Amgen, AbbVie/Allergan, Alexion, Samsung Bioepis, Biogen, Boehringer Ingelheim, Iveric Bio, Novartis, Roche, Bayer, Regeneron, Pfizer, Astellas, Nanoscope, Janssen, ssCenterVue, Optos, Heidelberg Notal Vision, Eyepoint, Character, and OTx and honoraria from Novartis, Roche, Optos, and Heidelberg. Chao Li and Caroline R. Baumal are employees of Apellis and may hold stock or stock options. Birva K. Shah and Kensington A. Hatcher are former employees of Apellis and may hold stock or stock options. Srinivas Sai Kondapalli has received speaker honoraria from Regeneron and is an owner of Rinsada.
Ethical Approval
As this was a retrospective analysis, institutional review board approval was not required. For the OAKS and DERBY studies, study protocols were approved by institutional review boards or ethics committees at each site. Both studies adhered to the Declaration of Helsinki. All patients who participated in the OAKS and DERBY studies provided written informed consent.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Arrigo A, Aragona E, Battaglia O, et al. Outer retinal tubulation formation and clinical course of advanced age-related macular degeneration. Sci Rep. 2021;11:14735.CrossRefPubMedPubMedCentral
2.
Dolz-Marco R, Litts KM, Tan ACS, Freund KB, Curcio CA. The evolution of outer retinal tubulation, a neurodegeneration and gliosis prominent in macular diseases. Ophthalmology. 2017;124:1353–67.CrossRefPubMed
3.
Zweifel SA, Engelbert M, Laud K, Margolis R, Spaide RF, Freund KB. Outer retinal tubulation: a novel optical coherence tomography finding. Arch Ophthalmol. 2009;127:1596–602.CrossRefPubMed
4.
Schaal KB, Freund KB, Litts KM, Zhang Y, Messinger JD, Curcio CA. Outer retinal tubulation in advanced age-related macular degeneration: optical coherence tomographic findings correspond to histology. Retina. 2015;35:1339–50.CrossRefPubMedPubMedCentral
5.
Braimah IZ, Dumpala S, Chhablani J. Outer retinal tubulation in retinal dystrophies. Retina. 2017;37:578–84.CrossRefPubMed
6.
Goldberg NR, Greenberg JP, Laud K, Tsang S, Freund KB. Outer retinal tubulation in degenerative retinal disorders. Retina. 2013;33:1871–6.CrossRefPubMedPubMedCentral
7.
Lee JY, Folgar FA, Maguire MG, et al. Outer retinal tubulation in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmology. 2014;121:2423–31.CrossRefPubMed
8.
Hariri A, Nittala MG, Sadda SR. Outer retinal tubulation as a predictor of the enlargement amount of geographic atrophy in age-related macular degeneration. Ophthalmology. 2015;122:407–13.CrossRefPubMed
Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology. 2020;127:186–95.CrossRefPubMed
11.
Hatcher KA, Shah BK, Burch M, Kondapalli SSA, Baumal CR. Outer retinal tubulation in geographic atrophy. Ophthalmic Surg Lasers Imaging Retina. 2024;55:448–51.CrossRefPubMed
12.
Hatcher KA, Shah BK, Yu S, Baumal CR, Sadda S. Outer retinal tubulation and vision in geographic atrophy: a natural history analysis from the phase 3 OAKS and DERBY trials. Ophthalmic Surg Lasers Imaging Retina. 2025;56:228–30.CrossRefPubMed
13.
Heier JS, Lad EM, Holz FG, et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023;402:1434–48.CrossRefPubMed
14.
Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye (Lond). 1988;2(Pt 5):552–77.CrossRefPubMed
15.
Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren CM. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014;121:1079–91.CrossRefPubMed
16.
Bakri SJ, Bektas M, Sharp D, Luo R, Sarda SP, Khan S. Geographic atrophy: mechanism of disease, pathophysiology, and role of the complement system. J Manag Care Spec Pharm. 2023;29:S2–11.PubMed
17.
Chakravarthy U, Bailey CC, Scanlon PH, et al. Progression from early/intermediate to advanced forms of age-related macular degeneration in a large UK cohort: rates and risk factors. Ophthalmol Retina. 2020;4:662–72.CrossRefPubMed
18.
Vallino V, Berni A, Coletto A, et al. Structural OCT and OCT angiography biomarkers associated with the development and progression of geographic atrophy in AMD. Graefes Arch Clin Exp Ophthalmol. 2024;262:3421–36.CrossRefPubMedPubMedCentral
19.
Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125:369–90.CrossRefPubMed
20.
Crass RL, Prem K, Gaudreault F, et al. Pharmacokinetic/pharmacodynamic analysis of geographic atrophy lesion area in patients receiving pegcetacoplan treatment or sham. CPT Pharmacometrics Syst Pharmacol. 2025;14:257–67.CrossRefPubMed
21.
Fleckenstein M, Schmitz-Valckenberg S, Adrion C, et al. Progression of age-related geographic atrophy: role of the fellow eye. Invest Ophthalmol Vis Sci. 2011;52:6552–7.CrossRefPubMed
22.
Grassmann F, Fleckenstein M, Chew EY, et al. Clinical and genetic factors associated with progression of geographic atrophy lesions in age-related macular degeneration. PLoS ONE. 2015;10:e0126636.CrossRefPubMedPubMedCentral
23.
Lindblad AS, Lloyd PC, Clemons TE, et al. Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26. Arch Ophthalmol. 2009;127:1168–74.CrossRefPubMed
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