The Issue of End Point Discordance in Dry Age-Related Macular Degeneration: How Might Clinical Trials Demonstrate a Functional Benefit?

Age-related macular degeneration (AMD) is a disorder of the macula characterized in its early and intermediate stages by the presence of drusen and pigmentary abnormalities in the macular region of the retina. Subsequently, a high proportion of such eyes demonstrate regions of loss of retinal pigment epithelium, photoreceptors, and the underlying choriocapillaris, a late-stage manifestation termed geographic atrophy (GA) or advanced atrophic AMD.1Fang V. Gomez-Caraballo M. Lad E.M. Biomarkers for nonexudative age-related macular degeneration and relevance for clinical trials: a systematic review.Mol Diagn Ther. 2021; 25: 691-713Crossref PubMed Scopus (4) Google Scholar The other common late-stage manifestation of AMD is macular neovascularization, which benefits from treatment with anti–vascular endothelial growth factor therapy.2Rein D.B. Wittenborn J.S. Burke-Conte Z. et al.Prevalence of age-related macular degeneration in the US in 2019.JAMA Ophthalmol. 2022; 140: 1202-1208Crossref PubMed Scopus (10) Google Scholar Unlike macular neovascularization, no treatments have been approved for GA, with predictions that visual impairment and blindness resulting from this condition will continue to rise.3Wong W.L. Su X. Li X. et al.Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.Lancet Glob Health. 2014; 2: e106-e116Abstract Full Text Full Text PDF PubMed Scopus (2757) Google Scholar During the past decade, we have seen the failure of numerous phase 1 through 3 clinical trials of GA and of intermediate AMD addressing a variety of mechanisms of action including neuroprotection, visual cycle modulation, cardiolipin stabilization, vasodilation, antiamyloid β, and cell replacement therapy.4Kim J.B. Lad E.M. Therapeutic options under development for nonneovascular age-related macular degeneration and geographic atrophy.Drugs Aging. 2021; 38: 17-27Crossref PubMed Scopus (6) Google Scholar However, several phase 3 clinical trials recently demonstrated a slowing in the progression of GA growth using complement inhibition strategies.5Wykoff C.C. Treatment of geographic atrophy secondary to AMD with pegcetacoplan: two-year outcomes from the randomized phase 3 DERBY and OAKS trials. AAO, Chicago, IL2022Google Scholar,6Khanani A. GATHER2 phase 3 efficacy results. AAO, Chicago, IL2022Google Scholar The OAKS and DERBY phase 3 trials of the intravitreal C3 inhibitor pegcetacoplan demonstrated reductions in GA growth of 16% to 22% over 24 months in treated eyes versus sham treatment, and this drug has received US Food and Drug Administration approval for use in routine clinical care.5Wykoff C.C. Treatment of geographic atrophy secondary to AMD with pegcetacoplan: two-year outcomes from the randomized phase 3 DERBY and OAKS trials. AAO, Chicago, IL2022Google Scholar The other newer contender is the anti-C5 avacincaptad pegol, which showed significant reductions in GA growth rate of 27% and 14%, respectively, over 12 months in the GATHER 1 and 2 phase 3 clinical trials.6Khanani A. GATHER2 phase 3 efficacy results. AAO, Chicago, IL2022Google Scholar In reviewing the evidence thus far, it is unlikely that the beneficial effect reported in either the OAKS and DERBY or the GATHER trials has arisen by chance. It is also unlikely that the omission of a true intravitreal sham injection in any of these trials has influenced the outcome. It is recognized that the mere fact of injecting vehicle as a sham control can influence the course of retinal degeneration in animal models.7Ward A.H. Siegwart Jr., J.T. Frost M.R. Norton T.T. The effect of intravitreal injection of vehicle solutions on form deprivation myopia in tree shrews.Exp Eye Res. 2016; 145: 289-296Crossref PubMed Scopus (18) Google Scholar However, no differential reduction in GA growth was observed in the large phase 3 Chroma and Spectri lampalizumab trials between sham and treatment arms, supporting the view that, at least in GA, this type of effect is not prominent. Despite the consistent reduction in GA growth across these trials in the active treatment arms, corresponding benefits in functional vision measurements have not been seen. In this editorial, we consider some of the reasons underpinning this lack of agreement. The OAKS and DERBY trials showed a disappointing lack of difference in all prespecified secondary functional end points of best-corrected visual acuity (BCVA), reading speed, functional reading independence index, and mean macular sensitivity.5Wykoff C.C. Treatment of geographic atrophy secondary to AMD with pegcetacoplan: two-year outcomes from the randomized phase 3 DERBY and OAKS trials. AAO, Chicago, IL2022Google Scholar The only glimmer of a relationship between the reduced GA expansion rates and functional benefit in treated eyes was observed in a subset with microperimetric assessments. Specifically, the number of new scotomatous points at the junctional zone between areas of atrophy and preserved retina occurred at lower frequency in treated eyes compared with eyes receiving sham treatment. Counterintuitively, statistical significance in the lower number of new scotomatous points was reached in the every-other-month treatment arm, but not in the monthly treatment arm in eyes treated with pegcetacoplan.5Wykoff C.C. Treatment of geographic atrophy secondary to AMD with pegcetacoplan: two-year outcomes from the randomized phase 3 DERBY and OAKS trials. AAO, Chicago, IL2022Google Scholar In the GATHER 1 and 2 phase 3 trials of avacincaptad pegol, a nonsignificant trend of better BCVA was reported in treated eyes compared with those receiving placebo.6Khanani A. GATHER2 phase 3 efficacy results. AAO, Chicago, IL2022Google Scholar Taken together, these exploratory analyses of the aforementioned trials suggest a benefit over placebo, possibly in subgroups of patients, over the 2-year period. To understand the discordance between retinal morphologic features and function, we should consider the modifiers of GA growth. The meta-analysis of robust epidemiologic studies by Colijn et al8Colijn J.M. Liefers B. Joachim N. et al.Enlargement of geographic atrophy from first diagnosis to end of life.JAMA Ophthalmol. 2021; 139: 743-750Crossref PubMed Scopus (10) Google Scholar revealed differences in growth rate between populations and noncontemporaneously recruited cohorts even within populations. Geographical location, as well as changes in diet and other health style modifications may have contributed to these differences in GA expansion rates.8Colijn J.M. Liefers B. Joachim N. et al.Enlargement of geographic atrophy from first diagnosis to end of life.JAMA Ophthalmol. 2021; 139: 743-750Crossref PubMed Scopus (10) Google Scholar Cohorts from trials and other studies analyzed for GA growth rates show that baseline GA area,9Sunness J.S. Margalit E. Srikumaran D. et al.The long-term natural history of geographic atrophy from age-related macular degeneration: enlargement of atrophy and implications for interventional clinical trials.Ophthalmology. 2007; 114: 271-277Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar foveal location, focality,10Fleckenstein M. Mitchell P. Freund K.B. et al.The progression of geographic atrophy secondary to age-related macular degeneration.Ophthalmology. 2018; 125: 369-390Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 11Shen L.L. Sun M. Grossetta Nardini H.K. Del Priore L.V. Progression of unifocal versus multifocal geographic atrophy in age-related macular degeneration: a systematic review and meta-analysis.Ophthalmol Retina. 2020; 4: 899-910Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 12Shen L.L. Sun M. Khetpal S. et al.Topographic variation of the growth rate of geographic atrophy in nonexudative age-related macular degeneration: a systematic review and meta-analysis.Invest Ophthalmol Vis Sci. 2020; 61: 2PubMed Google Scholar and fundus autofluorescence imaging patterns influence lesion expansion.13Fritsche L.G. Fleckenstein M. Fiebig B.S. et al.A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene.Invest Ophthalmol Vis Sci. 2012; 53: 2112-2118Crossref PubMed Google Scholar Larger extrafoveal multifocal lesions expand more rapidly compared with smaller, unifocal, foveal-involving lesions. Considering modifiers of functional change in GA, an analysis of 1901 patients with bilateral GA seen for routine care reported that the trajectory of visual loss was affected by whether it occurred in the better or worse eye.13Fritsche L.G. Fleckenstein M. Fiebig B.S. et al.A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene.Invest Ophthalmol Vis Sci. 2012; 53: 2112-2118Crossref PubMed Google Scholar In this cohort, the visual acuity (VA) of worse-seeing eyes decreased by 6.1 letters at 2 years and 10.9 letters at 5 years, whereas better-seeing eyes showed a steeper functional decline (12.4 letters at 2 years and 22.6 letters at 5 years). It is possible in the aforementioned study that the worse-seeing eyes had not adapted adequately to the scotoma at baseline and that better use of preserved retina in subsequent visits minimizes the observed loss in VA.14Sunness J.S. Applegate C.A. Haselwood D. Rubin G.S. Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease.Ophthalmology. 1996; 103: 1458-1466Abstract Full Text PDF PubMed Google Scholar Although VA seems to decline faster in the better-seeing eyes of an individual with bilateral GA,15Chakravarthy U. Bailey C.C. Johnston R.L. et al.characterizing disease burden and progression of geographic atrophy secondary to age-related macular degeneration.Ophthalmology. 2018; 125: 842-849Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar the trajectory of VA loss slows over time.16Sunness J.S. Gonzalez-Baron J. Applegate C.A. et al.Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration.Ophthalmology. 1999; 106: 1768-1779Abstract Full Text Full Text PDF PubMed Google Scholar In this context, it is worth noting that in one study on the natural history of GA that dichotomized eyes in to 2 groups–one with VA of 20/50 or better and the other VA worse than this level—40% of the former lost 3 Early Treatment Diabetic Retinopathy Study lines (equivalent to 15 letters) compared with 15% of the latter group.17Sunness J.S. Rubin G.S. Broman A. et al.Low luminance visual dysfunction as a predictor of subsequent visual acuity loss from geographic atrophy in age-related macular degeneration.Ophthalmology. 2008; 115 (8.e1–8.e2): 1480-1488Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar The drop in VA in low-luminance conditions (low-luminance deficit) is a significant parameter to observe in patients with good baseline VA. Unlike high-luminance VA, the low-luminance deficit may improve with treatment. Recovery of viable but dysfunctional photoreceptors may be measurable with tasks closer to threshold compared with standard Early Treatment Diabetic Retinopathy Study testing, which is performed at suprathreshold levels of luminance with ceiling effects. Data from a large clinical trial has shown that BCVA loss is more pronounced in unifocal compared with multifocal GA lesions and in smaller lesions as compared with larger lesions.18Heier J.S. Pieramici D. Chakravarthy U. et al.Visual function decline resulting from geographic atrophy: results from the Chroma and Spectri phase 3 trials.Ophthalmol Retina. 2020; 4: 673-688Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar It also has been shown that reading speed declines faster in smaller lesions18Heier J.S. Pieramici D. Chakravarthy U. et al.Visual function decline resulting from geographic atrophy: results from the Chroma and Spectri phase 3 trials.Ophthalmol Retina. 2020; 4: 673-688Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar and has a more acute slope of decline than BCVA.14Sunness J.S. Applegate C.A. Haselwood D. Rubin G.S. Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease.Ophthalmology. 1996; 103: 1458-1466Abstract Full Text PDF PubMed Google Scholar,16Sunness J.S. Gonzalez-Baron J. Applegate C.A. et al.Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration.Ophthalmology. 1999; 106: 1768-1779Abstract Full Text Full Text PDF PubMed Google Scholar Notably, the reading rate drops to fewer than 50 words/minute by 2 years in half of patients with GA.14Sunness J.S. Applegate C.A. Haselwood D. Rubin G.S. Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease.Ophthalmology. 1996; 103: 1458-1466Abstract Full Text PDF PubMed Google Scholar,16Sunness J.S. Gonzalez-Baron J. Applegate C.A. et al.Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration.Ophthalmology. 1999; 106: 1768-1779Abstract Full Text Full Text PDF PubMed Google Scholar However, binocular reading performance was similar to that of the better-seeing eye when tested by itself,19Künzel S.H. Lindner M. Sassen J. et al.Association of reading performance in geographic atrophy secondary to age-related macular degeneration with visual function and structural biomarkers.JAMA Ophthalmol. 2021; 139: 1191-1199Crossref PubMed Scopus (4) Google Scholar suggesting that the better-worse eye relationship does not extend to near VA-based measurements of function. Eyes with GA that also exhibited subretinal drusenoid deposits showed worse low luminance visual acuity compared with eyes without this feature.18Heier J.S. Pieramici D. Chakravarthy U. et al.Visual function decline resulting from geographic atrophy: results from the Chroma and Spectri phase 3 trials.Ophthalmol Retina. 2020; 4: 673-688Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Taking into consideration the factors that modify GA expansion and those that influence functional decline, it seems that the design of future AMD trials would benefit from a more targeted approach. Specifically, subfoveal lesions tend to exhibit both slower expansion as well as greater falls in BCVA compared with nonsubfoveal lesions.18Heier J.S. Pieramici D. Chakravarthy U. et al.Visual function decline resulting from geographic atrophy: results from the Chroma and Spectri phase 3 trials.Ophthalmol Retina. 2020; 4: 673-688Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Unifocal lesions grow more slowly than multifocal lesions, but show a greater decrease in BCVA and reading rate than multifocal lesions. We can therefore surmise that, to demonstrate differences in growth rate, clinical trial selection criteria should enrich for larger, rapidly expanding multifocal and extrafoveal GA lesions, as in the recent phase 3 anticomplement programs OAKS and DERBY and GATHER 1 and 2, which have revealed therapeutic benefit in this context. The alternative is to have very large, expensive trials for which it is difficult to achieve enrollment in a timely manner. Besides the caveats previously expressed, the currently used measures of visual function do not adequately capture the disability experienced by patients, and perhaps studies should be adequately powered to detect the impact of a treatment based on patient-reported outcomes.Taking into consideration the factors that modify GA expansion and those that influence functional decline, it seems that the design of future AMD trials would benefit from a more targeted approach. Taking into consideration the factors that modify GA expansion and those that influence functional decline, it seems that the design of future AMD trials would benefit from a more targeted approach. Trials may need to be enriched for populations who have not been targeted previously in order to achieve the goal of demonstrating differences in visual function. Notably, it would be reasonable to enroll patients who have good to moderate visual function and smaller unifocal subfoveal GA lesions. The differences in the modifiers of lesion expansion rates and visual decline are strong reasons to consider the discordance that has been observed between anatomic and functional outcomes. The design of a future trial of GA with the ability to show a meaningful difference in outcomes is certainly challenging, but—we hope—feasible.