Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in Western communities. AMD primarily affects people 50 and older, and due to the rapidly aging nature of the global population, the prevalence of AMD is expected to increase by over 46% and affect approximately 288 million people worldwide by 2040.1 Late AMD comes in 2 main forms: the dry form and the wet form, the latter of which is less common and involves abnormal blood vessel growth.2 Dry AMD is principally characterized by drusen in its early stages and progressive central vision loss caused by geographic atrophy (GA) in its late stages (Figure 1).3,4 As the disease progresses, retinal pigment epithelium (RPE) cells gradually degenerate and lead to the death of photoreceptor cells around the macula.4
Although there is no cure for dry AMD, considerable progress has been made regarding treatments that slow and prevent the progression of the disease. In 2023, pegcetacoplan (Syfovre; Apellis Pharmaceuticals) and avacincaptad pegol (Izervay; Astellas Pharma) were the first treatments to be approved by the US Food and Drug Administration (FDA) for GA secondary to dry AMD.5 With the recent addition of these therapies, it is essential to analyze the effects of current therapies and gain an understanding of their functional benefits for patients in a clinical setting.
Figure 1. Patient with dry AMD, numerous drusen and geographic atrophy. Image courtesy Katie Lachut-Yevich.
Complement Protein Inhibitors
The complement system plays essential roles in innate and adaptive immunity, contributing to inflammation and formation of the membrane attack complex (MAC) on cells. One of the 3 activation pathways, the alternative pathway, is associated with the development and progression of dry AMD. In dry AMD and the development of GA, dysregulation of the alternative pathway can induce local inflammatory processes and lead to the deposition of complement proteins such as C3b around the RPE area, thus contributing to the buildup of drusen.5-9
Both pegcetacoplan and avacincaptad pegol, the most recent FDA-approved medications for the treatment of dry AMD, act as complement inhibitors and aim to decrease the activity levels of the complement system. Randomized, multicenter clinical trials funded by the respective pharmaceutical companies assessed the efficacy of these drugs; these included OAKS and DERBY (for pegcetacoplan) and GATHER1 and GATHER2 (for avacincaptad pegol). In OAKS, pegcetacoplan treatment significantly slowed GA lesion growth by 21% when compared with sham at 12 months. Similarly, in GATHER1, avacincaptad pegol treatment reduced mean GA growth by 27% at 12 months.10,11
The mechanism of action for pegcetacoplan involves selectively targeting and binding the C3 and C3b complement proteins to regulate complement activation. As a result, there is less inflammation and tissue atrophy around the retina, thus slowing the degeneration of the RPE cells. From a visual function standpoint, preserving the retina, especially the macula in particular, allows patients to continue performing tasks that require more continuous areas of central vision such as reading and recognizing details in faces or objects.10 Preventing degeneration of the retina slows the loss of color vision and low-light vision for patients as well.
OAKS, the phase 3 trial conducted in 2018 on pegcetacoplan’s efficacy, confirmed the drug’s ability to slow GA lesion growth based on fundus autofluorescence imaging, but it did not find significant differences in key secondary visual function endpoints. Measured at the end of a 24-month treatment period, these assessments included change in monocular maximum reading speed of the study eye, change in mean functional reading independence index score, and change in mean threshold sensitivity of all points in the study eye by mesopic microperimetry.10 Thus, there is a discrepancy between quantitative improvements and its translation into clinically significant functional benefits for vision.
This disconnection between the 21% decrease in GA lesion growth rate and visual function outcome may be attributed to the location of GA.12 Studies have shown that the location of scotomas within the eye can influence maximum reading rate and other levels of visual function.13 Understanding that both location and size of GA lesions can play a role in determining whether a treatment like pegcetacoplan would be functionally beneficial for a patient is critical for clinicians, because this information can influence which treatment options would have greater efficacy over others in certain situations.
Despite the promising preliminary results, it is still not definitively clear whether pegcetacoplan is correlated with visual function benefits. Currently, the ongoing GALE extension study is evaluating the long-term efficacy of pegcetacoplan over a 36-month period.14 Between months 24 and 36, pegcetacoplan significantly reduced GA growth versus projected sham by 35% with monthly injection frequency, further affirming that the treatment preserves functional retinal tissue.15 Their visual function assessment, microperimetry, also presented clinically significant data—upon post hoc analysis, it was determined that patients had a 32% reduction in their chance of developing an absolute scotoma in the central subfield locus through month 36 of pegcetacoplan treatment, hence increasing preservation of the central macula.16 The impact of this suggests that patients receiving pegcetacoplan would be able to continue finding objects, recognizing faces, and reading finer print for a lengthened period of time.
Rather than targeting C3 and C3b, avacincaptad pegol inhibits the cleavage of complement factor C5 to effectively block terminal complement pathway activation and the subsequent MAC assembly.17 The GATHER1 trial, conducted over an 18-month period, revealed numerically better outcomes in low-luminance best-corrected visual acuity (BCVA) of patients undergoing avacincaptad pegol treatment as compared to the corresponding sham, suggesting that treated patients might have an easier time reading in low light conditions or viewing objects that require sharper vision.11 This difference in functional acuity was not clinically significant; however, a 27% significant reduction in the progression of GA was observed.18,19 In the discussion of the GATHER1 trial, researchers noted that the lack of difference in visual function effects can be attributed to the late onset of visual disability during the progression of dry AMD. Because significant vision loss does not begin to occur until past the 18-month time frame of the clinical trial, it was challenging to present accurate results in relation to effects on functional vision.11
When comparing the efficacy of pegcetacoplan and avacincaptad pegol against each other, a matching-adjusted indirect comparison (MAIC) meta-analysis of phase 3 trials published in 2024 demonstrated that monthly pegcetacoplan had a 30.4% statistically significant greater reduction in GA lesion growth compared to avacincaptad pegol at month 12.19 Both OAKS and DERBY and GATHER2 trials utilized change from baseline in normal luminance BCVA score as one of their functional endpoints, but a MAIC analysis of functional outcomes was not performed—this may be due to the fact that neither drug’s phase 3 trials demonstrated a statistically significant improvement in visual function after treatment. One of the explanations for this difference in efficacy is that the drugs inhibit complement factor proteins at different steps of the complement cascade, thus leading to unique downstream effects. C5 inhibition prevents the formation of the MAC, while C3 inhibition targets both upstream signaling mediators and downstream C5-derived proinflammatory effectors. Because C3 is located at the junction of all 3 pathways of complement activation, the upstream effects of the classical, MB-lectin, and alternative pathway can all be prevented with a C3 inhibitor.8 This comprehensive targeting ability may be the reason for the greater inhibition of lesion growth in patients who received pegcetacoplan.
Though there is not conclusive evidence comparing the extent of functional benefits provided by the 2 therapies, based on the data presented within the MAIC analysis of the drug’s clinical trials, one can hypothesize that pegcetacoplan may have a greater effect than avacincaptad pegol on preserving visual function, and patients may be able to protect their driving and reading abilities for a longer period of time.
Carotenoid Supplements
The mechanism of action for AREDS2 and other carotenoid formulations is still not fully understood at the molecular level. A 2020 pharmacology analysis shows that the AREDS2 formula targets several genes that affect a multitude of anti-inflammatory and antioxidant pathways, including HIF1 signaling, glutathione metabolism, and oxidative stress.20 From this, it can be derived that carotenoid supplementation may have protective properties against oxidative damage for RPE cells, thus preserving the patient’s central vision.
Lutein, zeaxanthin, and meso-zeaxanthin are the 3 macular carotenoids that constitute the macular pigment optical density (MPOD) within the retina, and they are often associated with maintaining optimal visual performance.21 In an effort to target and support the macular pigment, one of the most common treatments that patients with dry AMD are recommended is the over-the-counter AREDS2 oral supplement. Conducted in 2006, the Age-related Eye Disease Study 2 tested whether incorporating omega-3 fatty acids, lutein, and zeaxanthin to the original formula (vitamin C, vitamin E, beta-carotene, copper, and zinc) would be more effective in preventing the progression of dry AMD.22
At the end of this trial, researchers concluded that participants who took the AREDS2 formula containing lutein and zeaxanthin had a reduction in the risk of progression from intermediate to advanced dry AMD by about 25%. With the increased delay in progression toward late-stage dry AMD, patients may continue to maintain their retina health over several years and thus be able to continue performing tasks that require central vision. A 2020 study on visual function for patients with retinal drusen who took carotenoid supplements daily for 6 months demonstrated a statistically significant improvement in contrast sensitivity function when compared to the control group. This was determined through standardized contrast sensitivity testing with the VectorVision CSV-1000E device, where the increase in log contrast sensitivity values seen in patients on carotenoid supplementation was calculated through paired-samples t-testing.21
Lutein and zeaxanthin supplementation in general has been shown to improve visual processing speeds independent of dry AMD, as seen through increased critical flicker fusion thresholds and improved reaction times. A 2014 study evaluated these functions by comparing a group of healthy patients that was supplemented with 4 months of either zeaxanthin, lutein, and mixed omega-3 fatty acids, or solely zeaxanthin, against a placebo group. At the end of the 4-month period, MPOD in supplemented participants had a 0.09 increase in density, which was statistically significant. This increase correlated with a 3% improvement in visual reaction time, 18% decrease in coincidence anticipation errors at high speeds, and 3% increase in critical flicker fusion thresholds.23
Ocular Gene Therapy
Gene therapy trials are currently being conducted with a particular focus on targeting the complement cascade and preventing cell lysis. One therapy currently being studied is JNJ-1887 (formerly referred to as AAVCAGsCD59 or HMR59; Janssen Pharmaceuticals), a vector derived from an adeno-associated virus serotype 2 (AAV2), that is inserted into retinal cells to increase the expression of sCD59.24 This anti-inflammatory protein prevents the formation of the complement membrane attack complex on cell membranes and is often underexpressed in the RPE in patients with GA. By inhibiting membrane attack complex formation, this controls for excessive cellular damage and the progression of dry AMD. During a phase 1, multicenter, safety and tolerability study, patients within the high-dose treatment cohort showed continued decline of GA lesion growth rate over the course of 24 months.25 While functional changes for patients after treatment were not published for this therapy, these preliminary findings suggest that further investigation of JNJ-1887 is warranted.
GT005 (Gyroscope Therapeutics/Novartis), a recombinant adeno-associated viral vector encoding complement factor I, was another gene therapy that had been in the process of completing its phase 2 HORIZON and EXPLORE trials, but this development was discontinued in late 2023 due to the trials’ low likelihood of meeting their efficacy outcome.24,26 There is still an ongoing prospective, follow-up study (ORACLE) for patients who have previously received GT005, evaluating the long-term safety of this therapy 5 years after administration.27
RPE cell therapy
Since the 1990s, scientists have been studying how to perform a successful, effective RPE transplantation for patients with dry AMD. The most recent therapies involve human embryonic stem cell (hESC)–derived RPE cell suspension transplantation. This involves surgically injecting a suspension of RPE cells as an allograft into the subretinal space of an eye in an attempt to replace the damaged cells and restore vision. In 2011, 9 patients with GA received an hESC–derived RPE cell transplant, and at 6 months post-transplantation, 4 patients had an improvement in BCVA of at least 15 letters, which is generally accepted as a clinically significant measure of improvement.28 Vision-related quality of life was measured through the National Eye Institute Visual Function Questionnaire 25 at various time points after transplantation. These assessments also showed improvement on the mental health and vision subscales for general and peripheral vision as well as near and distance activities, improving by 16 to 25 points several months after transplantation. Thus, hESC-derived cells can be well tolerated with medium-term to long-term safety.28
OpRegen (Lineage Cell Therapeutics) is another allogeneic ESC-based therapy under development that injects RPE cells into the subretinal space.26 The results from OpRegen’s phase 1/2a trial demonstrate a numerical improvement of an average of 6 letters in change in BCVA as well as a 2-point average increase in National Eye Institute Visual Function Questionnaire 25 quality of life scores for all cohorts of patients, with effects observed through 24 months following a single administration.29 These are not statistically significant differences, but it shows promising potential for this cell-based product to improve vision-related quality of life for patients with GA secondary to dry AMD. Currently, OpRegen is recruiting participants for their phase 2a GAlette trial to further evaluate the therapy’s efficacy.30
Other formulations and methods of transplantation, including ES cell-derived RPE cell sheets and induced pluripotent stem cell–derived RPE/photoreceptor cell complexes, are currently being studied in animal models and phase 1 clinical trials. Visual acuity improvement has been reported in some patients after cell sheet transplantation, but no other measures of visual function have been studied.24
Conclusions and Future Considerations
There are several promising therapies for patients who are affected by dry AMD. The progressive nature of the disease and its interference with central vision can have significant negative effects on the quality of life and visual function of patients. With the emergence of the first FDA-approved treatments for GA, it is important to consider functional outcomes of the therapies beyond GA lesion growth to provide informed, comprehensive care for patients. As clinical trials continue to develop new therapies, placing an emphasis on functional secondary endpoints such as contrast sensitivity improvement, reading speed, and mobility can provide insight into the practical effects of treatment on a patient’s day-to-day life. RP
References
1. Fleckenstein M, Schmitz-Valckenberg S, Chakravarthy U. Age-related macular degeneration: a review. JAMA. 2024;331(2):147-157. doi:10.1001/jama.2023.26074
2. Nadeem A, Malik IA, Shariq F, et al. Advancements in the treatment of geographic atrophy: focus on pegcetacoplan in age-related macular degeneration. Ann Med Surg (Lond). 2023;85(12):6067-6077. doi:10.1097/MS9.0000000000001466
3. National Eye Institute. Age-related macular degeneration (AMD). National Institutes of Health. June 22, 2021. Accessed February 4, 2025. https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration
4. Stahl A. The diagnosis and treatment of age-related macular degeneration. Dtsch Arztebl Int. 2020;117(29-30):513-520. doi:10.3238/arztebl.2020.0513
5. Day-Storms, J. FDA approval of Syfovre (pegcetacoplan) and Izervay (avacincaptad pegol) reshapes management of GA. American Health and Drug Benefits. September 2023. Accessed February 4, 2025. https://ahdbonline.com/issues/2023/september-2023-vol-16-payers-guide/3291-fda-approval-of-syfovre-pegcetacoplan-and-izervay-avacincaptad-pegol-reshapes-management-of-ga
6. Armento A, Ueffing M, Clark SJ. The complement system in age-related macular degeneration. Cell Mol Life Sci. 2021;78(10):4487-4505. doi:10.1007/s00018-021-03796-9
7. 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(5-a Suppl):S2-S11. doi:10.18553/jmcp.2023.29.5-a.s2
8. Bradley DT, Zipfel PF, Hughes AE. Complement in age-related macular degeneration: a focus on function. Eye (Lond). 2011;25(6):683-693. doi:10.1038/eye.2011.37
9. Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9(10):729-740. doi:10.1038/nri2620
10. 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(10411):1434-1448. doi:10.1016/S0140-6736(23)01520-9
11. Patel SS, Lally DR, Hsu J, et al. Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial. Eye (Lond). 2023;37(17):3551-3557. doi:10.1038/s41433-023-02497-w
12. Csaky KG, Miller JML, Martin DF, Johnson MW. Drug approval for the treatment of geographic atrophy: how we got here and where we need to go. Am J Ophthalmol. 2024;263:231-239. doi:10.1016/j.ajo.2024.02.021
13. Sunness JS, Applegate CA, Haselwood D, Rubin GS. Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease. Ophthalmology. 1996;103(9):1458-1466. doi:10.1016/s0161-6420(96)30483-1
14. An Extension Study to Evaluate the Long-term Safety and Efficacy of Pegcetacoplan (APL-2) in Subjects With Geographic Atrophy Secondary to AMD (GALE). (2024, June 26). [Government website]. Clinical Trials. https://clinicaltrials.gov/study/NCT04770545
15. Abbey AM, Wykoff CC, Heier JS, et al. Long-term efficacy and safety of pegcetacoplan over 36 months including 12-month results of the GALE open-label extension study. Invest Ophthalmol Vis Sci. 2024;65(7):380.
16. Gallagher J. Pegcetacoplan an effective treatment for subfoveal GA. Retinal Physician. October 18, 2024. Accessed February 12, 2025. https://www.retinalphysician.com/issues/2024/october/pegcetacoplan-treatment-for-subfoveal-ga/
17. Kim BJ, Mastellos DC, Li Y, Dunaief JL, Lambris JD. Targeting complement components C3 and C5 for the retina: key concepts and lingering questions. Prog Retin Eye Res. 2021;83:100936. doi:10.1016/j.preteyeres.2020.100936
18. Spaide RF, Vavvas DG. Complement inhibition for geographic atrophy: review of salient functional outcomes and perspective. Retina. 2023;43(7):1064-1069. doi:10.1097/IAE.0000000000003796
19. Zarbin MA, Hahn P, Eichenbaum D, et al. Pegcetacoplan vs avacincaptad pegol in geographic atrophy: an anchored matching-adjusted indirect comparison of three phase 3 trials. Invest Ophthalmol Vis Sci. (2024);65(7):6487.
20. Wang M, Yu Y, Lou A, et al. (2020). A systemic pharmacology analysis of the Age-related Eye Disease Study 2 (AREDS2) formula and its role in preventing age-related macular degeneration (AMD). Invest Ophthalmol Vis Sci. 2020;61(7):4923.
21. Davey PG, Henderson T, Lem DW, Weis R, Amonoo-Monney S, Evans DW. Visual function and macular carotenoid changes in eyes with retinal drusen—an open-label randomized controlled trial to compare a micronized lipid-based carotenoid liquid supplementation and AREDS-2 formula. Nutrients. 2020;12(11):3271. doi:10.3390/nu12113271
22. National Eye Institute. Age-related eye disease studies (AREDS/AREDS2): major findings. National Institutes of Health. December 3, 2024. Accessed February 4, 2025. https://www.nei.nih.gov/research/clinical-trials/age-related-eye-disease-studies-aredsareds2/about-areds-and-areds2
23. Bovier ER, Renzi LM, Hammond BR. A double-blind, placebo-controlled study on the effects of lutein and zeaxanthin on neural processing speed and efficiency. PLoS One. 2014;9(9):e108178. doi:10.1371/journal.pone.0108178
24. Trincão-Marques J, Ayton LN, Hickey DG, et al. Gene and cell therapy for age-related macular degeneration: A review. Surv Ophthalmol. 2024;69(5):665-676. doi:10.1016/j.survophthal.2024.05.002
25. Heier JS, Cohen MN, Chao DL, et al. Phase 1 study of JNJ-81201887 gene therapy in geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2024;131(12):1377-1388. doi:10.1016/j.ophtha.2024.06.013
26. de Oliveira Figueiredo EC, Bucolo C, Eandi CM. Therapeutic innovations for geographic atrophy: A promising horizon. Curr Opin Pharmacol. 2024;78:102484. doi:10.1016/j.coph.2024.102484
27. ORACLE: a long-term follow-up study to evaluate the safety of GT005 in participants with geographic atrophy secondary to age-related macular degeneration treated in a Gyroscope-sponsored antecedent study. ClinicalTrials.gov Identifier: NCT05481827. Updated March 22, 2024. Accessed February 4, 2025.
28. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell–derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385(9967):509-516. doi:10.1016/S0140-6736(14)61376-3
29. Safety and efficacy study of OpRegen for treatment of advanced dry-form age-related macular degeneration. ClinicalTrials.gov Identifier: NCT02286089. Updated January 8, 2025. Accessed February 4, 2025. ).
30. A study to optimize subretinal surgical delivery and to evaluate safety and activity of OpRegen in participants with geographic atrophy secondary to age-related macular degeneration (GAlette). ClinicalTrials.gov Identifier: NCT05626114. Updated January 8, 2025. Accessed February 4, 2025.
