Geographic atrophy (GA) is an advanced form of nonexudative age-related macular degeneration (AMD) and a major cause of irreversible central vision loss in older adults. GA results in progressive loss of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris, leading to expanding atrophic lesions that negatively affect vision and quality of life.
Recent research suggests that dysregulation of the complement system plays a central role in chronic inflammation and retinal damage in GA.1 Oxidative stress, mitochondrial dysfunction, and metabolic impairment of the RPE also contribute to disease progression.¹ These insights have guided the development of therapeutic approaches.
Pegcetacoplan (Syfovre; Apellis Pharmaceuticals), an intravitreal C3 inhibitor, was the first therapy approved for GA secondary to AMD. It reduces downstream complement activation, including membrane attack complex (MAC) formation.2 In phase 2 and 3 trials, monthly and every-other-month dosing demonstrated modest but consistent reductions in lesion growth over 12 to 24 months, with monthly dosing associated with higher rates of conversion to exudative AMD.2,3 Rare cases of nonarteritic anterior ischemic optic neuropathy (~0.1%) and intraocular inflammation (approximately 1% to 2%) have been reported in long-term follow-up.4
Avacincaptad pegol (Izervay; Astellas), an intravitreal C5 inhibitor, selectively blocks terminal complement activation. Approval was supported by the GATHER1 and GATHER2 trials, which showed reductions in lesion growth ranging from 14% to 30% depending on study and time point.5-6 Acute increases in intraocular pressure occurred in 3% of eyes; 2.03% converted to neovascular AMD, with no reported cases of endophthalmitis, intraocular inflammation, or NAION in safety analyses.7 Together, these agents established complement inhibition as a therapeutic strategy for GA and serve as a reference point for emerging investigational therapies.
Beyond the 2 approved complement inhibitors, a diverse range of therapeutic approaches is currently under investigation for GA. These strategies include selective inhibition of specific complement pathways; therapies targeting mitochondrial dysfunction and cellular bioenergetics; gene therapies designed to restore endogenous complement regulation or provide sustained inhibition; and cell-based therapies intended to replace dysfunctional RPE and support photoreceptor survival. Collectively, these programs reflect a shift toward more precise, durable, and potentially function-preserving interventions.
Targeted Approaches
Vonaprument (formerly ANX007; Annexon) is an intravitreal monoclonal antibody targeting C1q. Studies suggest that classical complement activation contributes to synaptic loss and retinal degeneration in GA. By selectively inhibiting the classical complement pathway, it may reduce inflammatory damage while preserving the alternative and lectin pathways.
Vonaprument is currently being studied in the global phase 3 ARCHER II trial, which has enrolled more than 630 patients. Participants are randomized to receive monthly injections of the drug or a sham procedure, with the main goal of preventing a loss of at least 15 letters on a standard eye chart over 12 months. Secondary measures include low-luminance visual acuity and photoreceptor integrity. Top-line data from ARCHER II are expected in the second half of 2026.8
Mitochondrial-targeted therapy is another approach under investigation for GA. Elamipretide (Stealth BioTherapeutics) is a mitochondrial-targeted peptide that stabilizes cardiolipin within the inner mitochondrial membrane, improving cellular bioenergetics and reducing oxidative stress. The phase 2 ReCLAIM-2 trial emphasized functional outcomes, such as low-luminance visual acuity and reduction in lesion growth, with secondary structural analyses.9 Although the trial did not meet its primary endpoints, some patients demonstrated functional improvements, supporting further study.10 The phase 3 ReNEW and ReGAIN trials are currently evaluating the efficacy and safety of once-daily, self-administered subcutaneous elamipretide in approximately 360 patients with dry AMD.11
Gene Therapy
Gene therapy offers the potential for long-term benefit by targeting underlying disease mechanisms with a single or limited number of treatments. JNJ-81201887 (formerly JNJ-1887 or AAVCAGsCD59) is being developed by Janssen for GA secondary to AMD. This therapy uses an adeno-associated viral (AAV) vector to increase retinal expression of a soluble form of CD59, an endogenous inhibitor of the MAC, with the goal of protecting retinal cells and slowing disease progression. Following a phase 1 study, the program received fast track designation from the US Food and Drug Administration (FDA). The therapy is currently being evaluated in the phase 2b PARASOL trial, which is assessing change in GA lesion growth compared with sham control after a single intravitreal injection.12
CTx001 (Complement Therapeutics) is an AAV-based gene therapy that delivers a truncated version of complement receptor 1 (mini-CR1), intended to modulate both the classical and alternative complement pathways. The FDA has cleared the investigational new drug application, allowing initiation of the first-in-human Opti-GAIN phase 1/2 trial to evaluate safety, tolerability, and preliminary efficacy at multiple centers in the United States and United Kingdom.13 The trial design was informed by i-GAIN, a natural history study of more than 230 participants that characterized biomarkers and GA progression.
Sanofi’s SAR446597 targets 2 components of the complement cascade—C1s in the classical pathway and factor Bb in the alternative pathway. The therapy is delivered via a single intravitreal injection and encodes 2 therapeutic antibody fragments to suppress complement activity in the retina. By inhibiting both pathways, SAR446597 seeks to reduce chronic retinal damage while potentially eliminating the need for repeated injections. The FDA has granted fast track designation to this program,14 and a phase 1/2 trial began enrolling patients in the fall of 2025.15
In January 2026, Ocugen reported preliminary 12-month data (~50% of patients evaluated to date) from the second stage of the phase 1/2 ArMaDa clinical trial evaluating OCU410 (AAV5-RORA), its novel modifier gene therapy for GA.16 Fifty-one patients were randomized to medium or high subretinal doses or to an untreated control group. The preliminary data indicated a 46% reduction in lesion growth in treated eyes vs control, with medium-dose eyes achieving a 54% reduction. Photoreceptor and RPE preservation were also observed, with ellipsoid zone loss 60% slower in treated eyes compared with fellow eyes. No OCU410-related serious adverse events were reported. Completion of ArMaDa is expected later in 2026, according to Ocugen.17
Cell Therapy
Beyond complement modulation and gene-based strategies, several programs are pursuing cell-based approaches that aim to restore retinal structure by replacing lost or dysfunctional RPE within areas of atrophy.
OpRegen (RG6501) is being developed by Lineage Cell Therapeutics in collaboration with Roche/Genentech. It consists of allogeneic human RPE cells delivered via a single subretinal injection.Early phase 1/2a studies demonstrated acceptable safety and suggested structural and functional benefit in a subset of patients, supporting advancement into the ongoing phase 2a GAlette trial, which is evaluating surgical delivery and preliminary efficacy. The program has received regenerative medicine advanced therapy designation from the FDA.18,19
Regenerative Patch Technologies is also developing an allogeneic, bioengineered RPE cell implant for GA. In a completed phase 1/2a study, 27% of implanted eyes gained more than 5 letters of visual acuity compared with 7% of untreated fellow eyes, while vision loss greater than 5 letters occurred more frequently in nonimplanted eyes. Building on these findings, the company initiated the phase 2b PATCH AMD trial in December 2025, a randomized, assessor-masked, multicenter study designed to further evaluate safety and efficacy in patients with less advanced disease.20
Conclusion
The GA treatment landscape is evolving rapidly. After decades without disease-modifying options, the approval of pegcetacoplan and avacincaptad pegol represent important milestones. However, challenges remain, including chronic dosing, variable patient response, and the risk of conversion to exudative AMD. Emerging therapies aim to address these limitations through selective complement modulation, gene therapy–based durability, and mitochondrial-targeted strategies.
As the pipeline advances, clinical decision-making will increasingly require balancing structural efficacy with patient-centered considerations such as injection burden, functional goals, cost, and access to care. Incorporating functional and patient-reported outcomes may better capture clinically meaningful benefit. Ultimately, success will depend not only on slowing lesion expansion but also on preserving vision in ways that meaningfully improve patients’ lives. RP
References
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2. 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
3. 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 (FILLY). Ophthalmology. 2020;127(2):186–195. doi:10.1016/j.ophtha.2019.09.008
4. Wykoff CC, Holz FG, Chiang A, et al. Pegcetacoplan treatment for geographic atrophy in age‑related macular degeneration over 36 months: data from OAKS, DERBY, and GALE. Am J Ophthalmol. 2025;276:350‑364. doi:10.1016/j.ajo.2025.04.016.
5. Khanani AM, Wiseberg P, Luo T, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration (GATHER1): a randomized pivotal phase 2/3 trial. Ophthalmology. 2020. doi:10.1016/j.ophtha.2020.07.008
6. Khanani AM, Josephs KA, Dugel PU, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomized, double-masked, phase 3 trial. Lancet. 2023;402(10411):1449–1458. doi:10.1016/S0140-6736(23)01583-0
7. Abou‑Samra A, Barazi MD, Abbas A, et al. Real‑world experience of geographic atrophy treatment with avacincaptad pegol. J VitreoRetinal Diseases. 2025;9(6):784‑787. doi:10.1177/24741264251367100.
8. Vonaprument selected for EMA pilot study. Retinal Physician. August 8, 2025. Accessed February 12, 2026. https://www.retinalphysician.com/news/2025/vonaprument-selected-for-ema-pilot-study/
9. ReCLAIM-2: elamipretide in subjects with dry AMD or geographic atrophy. Clinicaltrials.gov identifier: NCT03891875. Updated July 12, 2024. Accessed February 12, 2026. https://clinicaltrials.gov/study/NCT03891875
10. Ehlers JP, Hu A, Boyer D, et al. ReCLAIM-2: a randomized phase II clinical trial evaluating elamipretide in age-related macular degeneration, geographic atrophy growth, visual function, and ellipsoid zone preservation. Ophthalmol Sci. 2024;5(1):100628. doi:10.1016/j.xops.2024.100628
11. Stealth BioTherapeutics announces achievement of 50% enrollment target in phase 3 ReNEW study of elamipretide in patients with dry age-related macular degeneration. News release. March 13, 2025. Accessed February 12, 2026. https://stealthbt.com/stealth-biotherapeutics-announces-achievement-of-50-enrollment-target-in-phase-3-renew-study-of-elamipretide-in-patients-with-dry-age-related-macular-degeneration/
12. J&J Medical Connect. JNJ-81201887 medical information. April 30, 2025. Accessed February 12, 2026. https://www.jnjmedicalconnect.com/products/jnj-81201887/medical-content/parasol-phase-2-clinical-trial
13. FDA clears gene therapy trial for GA. Retinal Physician. October 8, 2025. Accessed February 12, 2026. https://www.retinalphysician.com/news/2025/fda-clears-gene-therapy-trial-for-ga/
14. Sanofi gene therapy targets GA. Retinal Physician. July 16, 2025. Accessed February 12, 2026. https://www.retinalphysician.com/news/2025/sanofi-gene-therapy-targets-ga/
15. A safety and efficacy study of a one-time intravitreal injection of SAR446597 in participants with geographic atrophy secondary to age-related macular degeneration. Clinicaltrials.gov identifier: NCT07215234. Updated February 10, 2026. Accessed February 12, 2026. https://clinicaltrials.gov/study/NCT07215234
16. OCU410 shows early efficacy in GA trial. Retinal Physician. January 20, 2026. Accessed February 12, 2026. https://www.retinalphysician.com/news/2026/ocu410-shows-early-efficacy-in-ga-trial/
17. Study to assess the safety and efficacy of OCU410 for geographic atrophy (ArMaDa). Clinicaltrials.gov identifier: NCT06018558. Updated December 15, 2025. Accessed February 12, 2026. https://clinicaltrials.gov/study/NCT06018558
18. Lineage Cell Therapeutics. OpRegen for dry AMD. Accessed February 12, 2026. https://lineagecell.com/products-pipeline/opregen/
19. 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); Adaptive Optics (AO) retinal imaging substudy in association with study GR44251. Clinicaltrials.gov identifier: NCT05626114. Updated January 15, 2026. Accessed February 12, 2026. https://clinicaltrials.gov/study/NCT05626114
20. First patients treated in PATCH AMD study. Retinal Physician. December 17, 2025. Accessed February 12, 2026. https://www.retinalphysician.com/news/2025/first-patients-treated-in-patch-amd-study/