Age-related macular degeneration (AMD) is a major cause of blindness worldwide and is expected to affect approximately 288 million people by 2040.1 In the United States (US), approximately 20 million people have AMD. As the population ages, the number of people affected continues to increase.1
AMD has 3 distinct stages: early, intermediate, and advanced.2 Advanced AMD includes both exudative (or wet) AMD, as well as atrophic AMD, also known as geographic atrophy (GA). GA is characterized by progressive and irreversible atrophy of the choriocapillaris as well as the retinal pigment epithelium and photoreceptors.3 Incident GA typically starts outside the foveal center. However, although a patient’s Snellen acuity might be good, they often report difficulties with contrast sensitivity and with reading, particularly in dim illumination. GA grows by 0.53 to 2.6 mm2/year (median, 1.78 mm2/year which is nearly ¾ of a disk area annually).4 GA currently accounts for approximately 20% of all people who are legally blind in the US, with median time to progression to legal blindness estimated to be 6.2 years.5,6
KEY TAKEAWAYS:
• While treatments like Syfovre and Izervay offer hope in slowing progression, none yet prevent or reverse geographic atrophy.
• Photobiomodulation therapy improves visual acuity and reduces GA development.
• Research is actively evolving across drug, biologic, and gene therapy platforms, with focus on improving efficacy, minimizing side effects, and targeting specific lesion types and progression stages.
Treatments for Intermediate AMD
Unlike neovascular AMD, for which many different anti-vascular endothelial growth factor (anti-VEGF) injections and photodynamic therapy with verteporfin are available, there are fewer options for patients with dry AMD. The Age-Related Eye Diseases Study (AREDS) research group demonstrated that the supplements given during AREDS and AREDS2 reduced the risk of progression from intermediate to late AMD (specifically wet AMD, but not GA) by 25% over 5 years. However, a recent post hoc analysis of AREDS and AREDS2 studies showed that while the AREDS and AREDS2 vitamins did not affect overall GA lesion growth rate, they did seem to slow progression of GA towards the central macula (termed “proximal growth”) by 35% to 36%.
In late 2024, the US Food and Drug Administration (FDA) approved LumiThera’s Valeda Light Delivery System, which uses photobiomodulation (PBM) to treat patients with intermediate AMD. PBM therapy involves application of visible to near-infrared light to eyes over multiple sessions, each session lasting a few minutes. The treatment is hypothesized to stimulate mitochondria, thereby improving retinal cell metabolic function. The LIGHTSITE III trial included a total of 100 participants and met its primary 13-month endpoint of improved best corrected visual acuity (BCVA) in the PBM vs sham group.
LIGHTSITE III also reported a benefit of PBM for the secondary outcome of reducing development of incident GA. At baseline, 6 PBM eyes (6.5%) and 5 sham eyes (9.1%) had evidence of GA. By month 13, an additional 5 sham eyes (10%) developed GA compared with 1 PBM eye (1.1%). Treatment was administered in a physician’s office and consisted of 9 sessions over 3 to 5 weeks, repeated every 4 months (ie, 27 office visits per year).7 This treatment is not covered by insurance.
First Treatments for Geographic Atrophy
In 2023, the FDA announced approval of an anti-complement component 3 (C3) pegylated-peptide, pegcetacoplan (Syfovre, Apellis Pharmaceuticals), the first ever treatment for GA.8 Later that year, avacincaptad pegol, a complement 5 (C5) inhibitor (Izervay, Astellas), was also approved by the FDA.9
Approval of Syfovre was a significant milestone in the treatment of GA, with approval based on the results of 2 phase 3 trials (OAKS and DERBY). In the OAKS study at 12 months, compared to sham, pegcetacoplan monthly slowed GA lesion growth by 21%, and treatment every other month (EOM) slowed GA lesion growth by 16%. In the DERBY trial, although statistical significance was not reached, at 12 months pegcetacoplan monthly and pegcetacoplan EOM slowed GA lesion growth by 12% and 11% respectively.10 Reduction in GA progression continued at 24 months.10
Even more encouraging, results from the GALE open-label extension study showed increasing efficacy with continuous pegcetacoplan treatment over 3 years in patients with GA. In the GALE study, monthly pegcetacoplan reduced growth of GA lesions by 35% with monthly dosing and 24% with EOM dosing. In a subgroup analysis, patients with non-subfoveal GA (typically those with good vision) treated with pegcetacoplan had reduction of GA growth by 42% with monthly dosing and 24% with EOM dosing compared to the sham arm.11 The GALE extension study was also the first to show a visual function benefit, with patients developing fewer scotomatous points on microperimetry with 36 months of both continuous monthly and EOM treatment compared to the sham group.12
Year 3 Results
The safety profile of pegcetacoplan in year 3 remained consistent with previously reported data. During the first year of GALE, the rate of choroidal neovascularization (CNV) was 7.1% (monthly) and 2.3% (EOM). There was 1 case of ischemic optic neuropathy in the monthly group between months 24 to 30, and 1 case of endophthalmitis between months 30 to 36. The rate of intraocular inflammation (IOI) was 0.26% per injection from months 0 to 36 (not including the 4 cases linked to the 2018 impurity). No events of retinal vasculitis have been observed in the Syfovre clinical trial program, following more than 24,000 injections to date.
Since pegcetacoplan became commercially available in 2023, 14 cases of severe retinal vasculitis following administration of the drug have been reported by the ASRS Research and Safety in Therapeutics (ReST) committee. All cases occurred after the first injection of pegcetacoplan, with median VA at the last follow-up visit being 20/200 (range: 20/70-NLP). Eight eyes (57%) had more than a 3-line decrease in VA at the final follow-up, while 6 eyes (43%) had more than a 6-line decrease in VA. One of the proposed mechanisms of the intraocular inflammation associated with pegcetacoplan is thought to be related to anti-PEG antibodies.
Given the rare nature of this adverse event, some retina specialists treat the worse eye with ½ dose pegcetacoplan and check the eye for inflammation within 3-4 weeks. If no inflammation or adverse reaction is seen, the worse seeing eye is then injected with the full pegcetacoplan dose followed with treatment in 1 or both eyes as indicated a month or so later.13
The GATHER 1/2 studies showed efficacy of avacincaptad pegol, a complement 5 inhibitor, in reducing GA progression over 12 and 18 months in patients with non-foveal GA. The GATHER 1 study, a phase 2/3 trial, showed a reduction of approximately 27% in both the 2 mg and 4 mg cohorts at 12 months.14 At 18 months, GA growth was reduced by 28% in the 2 mg cohort and 30% in the 4 mg cohort.15 GATHER2, a phase 3 trial, demonstrated a 14% difference in GA growth between avacincaptad pegol 2 mg and sham over 12 months.16 No cases of endophthalmitis or ischemic optic neuropathy events were seen at 12 months in GATHER1 or GATHER2. There was 1 case of intraocular inflammation in GATHER1. In GATHER1, over 12 months, CNV occurred in 9%, 9.6% and 2.7% of patients in the 2 mg, 4 mg and sham group respectively. In GATHER 2, CNV occurred in 7% of patients in the avacincaptad pegol 2 mg group vs 4% in the sham group.17
Current Clinical Research
While our 2 currently available treatments slow GA progression, there’s a need for agents that would ideally prevent or reverse GA—or that would slow GA progression to a greater degree. Targetting components of the complement cascade for GA remains an area of active research. BI 771716, developed by Boehringer Ingelheim, is a highly specific antibody fragment that inhibits C3 and C3b and has enhanced penetration across retinal layers. The drug met its primary safety endpoint after intravitreal administration of single and multiple doses 4 weeks apart in a phase 1 trial. A phase 2 trial is currently underway.18
Regeneron has a novel combination of a siRNA C5 inhibitor cemsidiran, initially developed for IgA nephropathy, along with a monoclonal antibody, pozelimab, to treat patients with GA. Unlike other drugs in development, this treatment is administered subcutaneously every 4 weeks. Two phase 3 trials are currently underway.19, 20
Gene Therapy: Longterm Benefits?
Gene therapy—another avenue being explored for GA—promises the possibility of long-term benefit through a single treatment. In 2017, Hemera Biosciences (Waltham, Massachusetts) conducted a gene therapy (AAVCAGsCD59) trial for dry AMD.21 Johnson & Johnson Innovative Medicine (Raritan, New Jersey) acquired the rights to HMR59 and named the drug JNJ-1887.
JNJ-1887 is an intravitreal injection of CD59, which prevents the formation of the membrane attack complex (MAC), the product at the end of the complement cascade.21 Increased MAC deposition has been shown to play a role in AMD development and progression.22 The phase 1 trial in GA enrolled 17 patients who were treated with 1 of the 3 doses of the study drug.23 All 3 doses met the primary safety endpoint over the 2-year follow-up period. Additionally, for eyes in the high-dose cohort, GA growth rate declined through 24 months, with a reduction in mean-square-root lesion growth from 0.211 mm at months 0 through 6 to 0.056 mm at months 18 through 24.24 JNJ-1887 is currently in a phase 2b clinical trial.25
Complement Therapeutics, a preclinical-stage biotechnology company, is developing CTx001, an adenovirus-associated vector (AAV) gene therapy expressing a soluble, truncated form of complement receptor 1 (mini-CR1). In vivo studies found a 60% reduction in MAC levels following CTx001 delivery, with no adverse findings reported.25 The phase 1 study will be enrolling in the latter half of 2025.
GT005 (Gyroscope/Novartis) is also a one-time AAV gene therapy that encodes complement factor I (CFI). The therapy is delivered using one of two methods: vitrectomy with subretinal delivery, or a subretinal delivery system that goes through the suprachoroidal space. Several trials evaluated GT005 in the treatment of GA.26,27 The phase 1/2 FOCUS trial enrolled 56 patients and safety data suggested that GT005 was well tolerated with no treatment-related serious adverse events.26 Additionally, 11 of the 13 patients treated with GT005 had increased CFI levels (mean increase of 122% vs baseline) that was sustained at week 29 and beyond.28 However, GT005 was discontinued by Novartis in September 2023, based on a recommendation from the independent Data Monitoring Committee (DMC). It concluded that overall data from the lead phase 2 HORIZON trial did not support continuation of the development.29
The current and emerging GA treatments offer hope to affected patients and demonstrate rapid, ongoing innovation in this field. Identifying the most suitable pathway to target these therapies; tailoring treatments to specific lesion types; and assessing their safety profile will guide future advancements in the field. OM
References
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2. Ferris FL, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration. Ophthalmol. 2013;120(4). doi:10.1016/j.ophtha.2012.10.036
3. Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol. 1995;39(5). doi:10.1016/S0039-6257(05)80092-X
4. Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmol. 2018;125(3):369-390. doi:10.1016/j.ophtha.2017.08.038
5. Chakravarthy U, Bailey CC, Johnston RL, et al. Characterizing disease burden and progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmol. 2018;125(6):842-849. doi:10.1016/j.ophtha.2017.11.036
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7. Boyer D, Hu A, Warrow D, et al. LIGHTSITE III: 13-month efficacy and safety evaluation of multiwavelength photobiomodulation in nonexudative (dry) age-related macular degeneration using the Lumithera Valeda light delivery system. Retina. 2024;44(3). doi:10.1097/IAE.0000000000003980
8. Pavluk L, Kaya M. FDA approves SYFOVRETM (pegcetacoplan injection) as the first and only treatment for geographic atrophy (GA), a leading cause of blindness. February 17, 2023. www. https://investors.apellis.com/news-releases/news-release-details/fda-approves-syfovretm-pegcetacoplan-injection-first-and-only. Accessed June 23, 2025.
9. Iveric Bio receives U.S. FDA approval for IZERVAYTM (avacincaptad pegol intravitreal solution), a new treatment for geographic atrophy. https://www.astellas.com/en/news/28281 Accessed June 23, 2025.
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. The Lancet. 2023;402(10411). doi:10.1016/S0140-6736(23)01520-9
11. SYFOVRE® (pegcetacoplan injection)continued to demonstrate increasing treatment effects over 3 years in patients with geographic atrophy (GA). November 4, 2023. https://investors.apellis.com/news-releases/news-release-details/syfovrer-pegcetacoplan-injection-continued-demonstrate-0. Accessed June 23, 2025.
12. SYFOVRE® (pegcetacoplan injection) preserved visual function at 36 months in GALE extension study in geographic atrophy (GA). June 10, 2024. https://investors.apellis.com/news-releases/news-release-details/syfovrer-pegcetacoplan-injection-preserved-visual-function-36. Accessed June 23, 2025.
13. Witkin AJ, Jaffe GJ, Srivastava SK, Davis JL, Kim JE. Retinal Vasculitis After Intravitreal Pegcetacoplan: Report from the ASRS research and safety in therapeutics (ReST) committee. J Vitreoretin Dis. 2024;8(1). doi:10.1177/24741264231220224
14. Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal 2/3 trial. Ophthalmol. 2021:128 (4)576-586. Vol 128. ; 2021. doi:10.1016/j.ophtha.2020.08.027
15. 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 (Basingstoke). 2023;37(17). doi:10.1038/s41433-023-02497-w.
16. Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. The Lancet. 2023;402(10411). doi:10.1016/S0140-6736(23)01583-0
17. Jaffe GJ, Khanani AM. Two studies to learn if avacincaptad pegol works and is safe in people with geographic atrophy: a plain language summary of the GATHER1 and GATHER2 studies. Immunotherapy. 2024;16(4). doi:10.2217/imt-2023-0274
18. Boehringer Ingelheim. A study to test how well different doses of BI 771716 are tolerated by people with an advanced form of age-related macular degeneration (AMD) called geographic atrophy. February 18, 2025. https://clinicaltrials.gov/study/NCT06006585?term=bi%20771716&rank=1.
19. Schliefer, LS. FDA approval and successful launch of Eylea HD. Presentation at J.P.Morgan Healthcare Conference. January 8, 2024. https://regeneronpharmaceuticalsinc.gcs-web.com/static-files/7dfdabe2-05d1-4145-b5c5-342cec0ce9c4.
20. https://regeneronpharmaceuticalsinc.gcs-web.com/static-files/7dfdabe2-05d1-4145-b5c5-342cec0ce9c4. Accessed June 23, 2025.
21. Intravitreal AAVCAGsCD59 for advanced dry age-related macular degeneration (AMD) with geographic atrophy (GA). May 10, 2021. ClinicalTrials.gov ID NCT04358471 (GA). https://clinicaltrials.gov/show/NCT04358471. Accessed June 23, 2025.
22. Desai D, Dugel PU. Complement cascade inhibition in geographic atrophy: a review. Eye (Basingstoke). 2022;36(2). doi:10.1038/s41433-021-01765-x
23. A study to evaluate intravitreal JNJ-81201887 (AAVCAGsCD59) compared to sham procedure for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). May 10, 2021. https://clinicaltrials.gov/show/NCT05811351. Accessed June 23, 2025.
24. 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. Ophthalmol. 2024;131(12):1377-1388. doi:10.1016/j.ophtha.2024.06.013
25. Keefe D, Munye M, Hasan R, Rathi S, Bishop P, Clark S. CTx001, a gene therapy for the treatment of geographic atrophy in aged-related macular degeneration. Invest Ophthalmol Vis Sci. 2023;64(8):3852.
26. FOCUS: A Phase I/II first in human study to evaluate the safety and efficacy of GT005 administered in subjects with dry AMD. https://www.clinicaltrials.gov/study/NCT03846193.
27. HORIZON: A phase II study to evaluate the safety and efficacy of two doses of GT005. https://clinicaltrials.gov/study/NCT04566445.
28. Gyroscope Therapeutics announces presentation of positive interim Phase I/II data for investigational gene therapy GT005 at Retina Society Annual Scientific Meeting. https://www.biospace.com/article/releases/gyroscope-therapeutics-announces-presentation-of-positive-interim-phase-i-ii-data-for-investigational-gene-therapy-gt005-at-retina-society-annual-scientific-meeting/.
29. Novartis. GT005 (PPY988): Development program in geographic atrophy. September 11, 2023 https://www.novartis.com/news/gt005-ppy988-development-program-geographic-atrophy. Accessed June 23, 2025.
