Geographic atrophy (GA) is the advanced stage of dry age-related macular degeneration (AMD) and a chronic, progressive, irreversible retinal degenerative disease. It is characterized by the gradual atrophy of the retinal pigment epithelium (RPE), photoreceptors, and the choriocapillaris, ultimately leading to progressive loss of central vision and impaired reading, facial recognition, and other fine visual functions. With nearly 5 million patients globally and a 20% prevalence rate in those over 85, the clinical urgency for effective intervention is paramount.

Before 2023, no treatment was available for this debilitating disease. Patients were encouraged to avoid risk factors for progression and directed to supplements and behaviors that reduce the development of advanced disease. Recent consensus identifies complement system dysregulation as the primary driver of chronic inflammation and tissue damage in GA. This has led to the successful commercialization of two first-in-class therapies. 
 

FDA-Approved Therapies for Geographic Atrophy (GA)

Now, the FDA has approved two drugs - Syfovre (pegcetacoplan) and Izervay (avacincaptad pegol) for GA.

| Pegcetacoplan (Syfovre) - Target Complement C3

Intravitreal pegcetacoplan (Syfovre; Apellis Pharmaceuticals, Inc.) was approved in February 2023, the first-ever treatment for GA due to dry AMD in the US. Pegcetacoplan is a pegylated complement C3 inhibitor peptide blocking the cleavage of C3 into C3a and C3b. It inhibits the central node of the complement cascade, preventing opsonization and formation of the membrane attack complex (MAC).

In 2025, it generated $587 million in net product revenue, commanding a 60% market share. [2] A next-generation combo (Syfovre + APL-3007) is currently in Phase 2, aiming for comprehensive complement suppression.

| Avacincaptad Pegol (Izervay®) - Target Complement C5

Avacincaptad pegol (Izervay; Astellas) is an RNA aptamer, a PEGylated oligonucleotide that binds to and inhibits complement protein C5. By inhibiting C5, avacincaptad pegol may prevent its cleavage to C5a and C5b, thus decreasing membrane attack complex (MAC) formation.

Since its approval in August 2023, Izervay has rapidly emerged as a strategic cornerstone of Astellas’ ophthalmology portfolio. According to official financial disclosures, Izervay generated 58.3 billion yen in global sales during the 2024 fiscal year (April 1, 2024 – March 31, 2025). [3] This momentum accelerated sharply into fiscal year 2025; sales for the first nine months alone (April 1, 2025 – December 31, 2025) reached 55.8 billion yen, nearly eclipsing the previous year’s total performance in just three quarters. [4]

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Related Articles: Complement Inhibitors as Therapeutic Agents 
 

Therapeutic Pipelines for GA Treatment

The approvals of Syfovre and Izervay marked a 0-to-1 breakthrough in GA treatment, shifting the condition from untreatable to manageable. However, these first-generation therapies have clear limitations: frequent intravitreal injections impose a significant patient burden, and their efficacy is largely confined to slowing anatomical lesion growth, often failing to address the primary goal of improving visual function.

This reality is accelerating the global R&D pipeline toward longer-acting, more precise, and function-oriented therapies. From established modalities like antibodies and peptides to emerging platforms such as siRNA and AAV-based gene therapies, a comprehensive, multi-layered therapeutic landscape is taking shape.

| Monoclonal Antibodies (mAbs)

The therapeutic strategy for GA is undergoing a pivotal shift: from relying solely on anatomical endpoints (lesion growth) toward prioritizing functional outcomes (vision preservation).

Vonaprument (ANX007, Annexon, Phase III): It is a first-in-class, non-pegylated antigen-binding fragment (Fab) designed to selectively inhibit C1q, the initiator of the classical complement pathway.

The Phase 2 ARCHER trial demonstrated significant advantages in maintaining Best Corrected Visual Acuity (BCVA) and Low Luminance Visual Acuity (LLVA). Currently, Vonaprument is in a global Phase 3 ARCHER II trial, with topline data anticipated in H2 2026. It has benn granted FDA Fast Track designation and EU Priority Medicines (PRIME) designation, underscoring its potential to address high unmet clinical needs. [5]

| Small Molecule Inhibitors

Small molecules represent a high-potential modality for GA treatment, leveraging superior tissue penetration and the critical advantage of oral administration to significantly improve patient adherence and reduce the burden of frequent intravitreal injections.

Tinlarebant (LBS-008, Belite Bio, Phase III)： Tinlarebant is a novel, once-a-day oral RBP4 antagonist designed to mitigate retinal toxicity by modulating the visual cycle. It limits vitamin A uptake, effectively reducing the accumulation of cytotoxic bisretinoids at the source.

Tinlarebant achieved a pivotal breakthrough in the global Phase 3 DRAGON trial for Stargardt disease (STGD1). Top-line data released in December 2025 demonstrated a significant reduction in lesion growth rate (~36%, p=0.0033), with consistent 33.6% improvement observed in the contralateral eye and a favorable safety profile. [6]

| Peptides

Moving beyond the complement pathway, peptide therapeutics represent a novel strategy in GA by addressing cellular metabolism. These agents balance high specificity with mature manufacturing profiles, shifting the therapeutic goal from inflammation control to the preservation of cellular health and energy homeostasis.

Elamipretide (Stealth BioTherapeutics, Phase III): Elamipretide is a first-in-class mitochondria-targeting peptide that restores mitochondrial structure and function. By improving the cellular bioenergetic profile and mitigating oxidative stress, it aims to preserve RPE and photoreceptor cell viability.

While the Phase 2 ReCLAIM-2 trial did not meet its primary endpoints for GA lesion progression or mean change in low-luminance visual acuity, it revealed critical structural benefits. Patients treated with subcutaneous elamipretide demonstrated a 43% reduction in ellipsoid zone (EZ) total attenuation at 48 weeks (P = 0.003) compared to placebo. [7] Elamipretide is currently in Phase 3 clinical trials (ReNEW and ReGAIN).

| AAV Gene Therapies

The AAV (adeno-associated viral) vector platform represents the most promising pathway to achieving long-term durability in GA treatment.

JNJ-81201887 (Janssen, Phase II): JNJ-81201887 is a recombinant AAV (AAVCAGsCD59) serotype 2 designed to express soluble CD59 (sCD59). As a potent endogenous protein, sCD59 inhibits the formation and accumulation of the membrane attack complex (MAC), thereby protecting retinal cells from complement-mediated lysis and cell death. Following positive Phase I data, the candidate was granted FDA Fast Track designation. It is currently being evaluated in the Phase IIb PARASOL trial, which compares the efficacy of a single intravitreal injection against a sham to measure its impact on the progression of GA lesions. [8]

OCU410 (AAV5-RORA, Ocugen, Phase II): OCU410, developed as a one-time gene therapy for patients with GA secondary to dry AMD, is an AAV5-based gene therapy delivering the RORA (retinoid-related orphan receptor alpha) gene. By acting as a nuclear receptor, RORA coordinates key biological pathways—including oxidative stress response, complement regulation, inflammation, and lipid metabolism—offering a holistic approach to disease modification rather than narrow pathway blockade. Twelve-month data from the Phase 2 ArMaDa trial highlighted its clinical potential, with the optimal (medium) dose achieving a 31% reduction in lesion growth ($p < 0.05$) and a 27% slower rate of ellipsoid zone (EZ) loss compared to controls. [9]

SAR446597 (Sanofi, Phase I/II): SAR446597 is a pioneering, one-time intravitreal gene therapy designed to address the underlying pathophysiology of GA. Recently granted FDA Fast Track designation, this therapy distinguishes itself through a unique dual-targeting mechanism: it delivers genetic material encoding two therapeutic antibody fragments that simultaneously inhibit C1s in the classical pathway and Factor Bb in the alternative pathway. [10]

CTX001 (Vertex & CRISPR Therapeutics, Phase II/III): CTX001 is an investigational AAV2-based gene therapy engineered to modulate both the classical and alternative complement pathways through the expression of mini-CR1. As a truncated and secreted form of Complement Receptor 1, mini-CR1 offers a distinct pharmacological advantage due to its small molecular footprint. This allows the protein to penetrate Bruch’s membrane, achieving a broad ocular biodistribution that encompasses both the retina and the choriocapillaris—areas critical to GA pathology. [11]

| SiRNAs

Cemdisiran (Regeneron, Phase III): Cemdisiran, a C5-targeting siRNA, is currently being evaluated in the Phase 3 SIENNA trial (NCT06541704) for GA. This study assesses the efficacy of Cemdisiran administered either as a subcutaneous monotherapy or in combination with pozelimab (a C5 monoclonal antibody), with the primary endpoint defined as the rate of GA lesion area growth measured via fundus autofluorescence. This combination regimen draws confidence from robust clinical precedents; in a Phase 3 trial for myasthenia gravis, the regimen demonstrated nearly 99% inhibition of complement activity, highlighting its potential for exceptionally deep and durable suppression of the C5 pathway. [12]

ADX 038 (ADARx Pharmaceuticals, Phase II): ADX-038 is an investigational siRNA therapeutic engineered to selectively silence Complement Factor B (CFB), a validated upstream driver of the alternative complement pathway. ADX-038 is currently undergoing multiple Phase 2 clinical trials to evaluate its safety and efficacy across a broad spectrum of complement-mediated diseases, including GA secondary to AMD, IgA nephropathy (IgAN), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH). [13]

| Cell Therapy & Nanoparticles

OpRegen (RG6501, Lineage Cell Therapeutics/Genentech/Roche, Phase II): OpRegen is a regenerative cell therapy involving the subretinal delivery of 200,000 allogeneic retinal pigment epithelium (RPE) cells designed to replace damaged retinal tissue. Results from the Phase 1 GAlette trial (NCT02286089) demonstrated significant, durable clinical benefits; at the 36-month follow-up, patients achieved a mean Best Corrected Visual Acuity (BCVA) gain of 6.2 letters, alongside sustained improvements in OCT-visualized structures, such as the external limiting membrane (ELM) and the RPE/drusen complex. The ongoing Phase 2a trial (NCT05626114) continues to evaluate the feasibility of subretinal surgical delivery and safety profiles, with a key focus on qualitative structural restoration of the retina as observed via OCT. [14]

AVD-104 (Aviceda Therapeutics, Phase II) : AVD-104 represents a unique therapeutic modality utilizing sialic acid-coated nanoparticles to orchestrate retinal homeostasis. Its dual-action mechanism involves recruiting complement factor H to cell membranes while binding Siglec receptors on macrophages, effectively dampening inflammatory and phagocytic activity. AVD-104 is currently under investigation in the Phase 2 SIGLEC trial (NCT05839041), comparing monthly intravitreal injections (low- vs. high-dose) against avacincaptad pegol (2 mg) over one year. Early results from Part 1 (n = 30) are highly encouraging, demonstrating a 48% reduction in GA lesion growth compared to fellow eyes. Furthermore, treated patients experienced a dose-dependent visual improvement of 4.8 to 6.5 letters three months post-injection, highlighting the candidate's potential for both anatomical stabilization and functional recovery in GA patients. [15]
 

Conclusion

The therapeutic landscape for GA is evolving rapidly. While the first wave of approved therapies marked a historic milestone, they are merely the starting point. To overcome the limitations of frequent injections and modest efficacy, the field is now shifting toward next-generation solutions. From durable gene therapies to more precise biological targets, these innovations are redefining the standard of care.
 

References:
[1] Retinal Physician. (2026). The Therapeutic Pipeline for Geographic Atrophy.
[2] Apellis Pharmaceuticals Reports Fourth Quarter and Full Year 2025 Financial Results https://investors.apellis.com/news-releases/news-release-details/apellis-pharmaceuticals-reports-fourth-quarter-and-full-year-7 
[3] Financial Results of Astellas for Fiscal Year 2024 https://www.astellas.com/content/dam/astellas-com/global/en/documents/financial-results/full-year-and-4q-fy2024-financial-results-en.pdf
[4] Financial Results of Astellas for the First Nine Months of FY2025 https://www.astellas.com/content/dam/astellas-com/global/en/confidential-documents/financial-results/3q2025_en.pdf 
[5] Annexon Announces Completion of Enrollment in Pivotal Phase 3 ARCHER II Trial of Vonaprument (formerly ANX007) for Dry Age-Related Macular Degeneration (AMD) with Geographic Atrophy https://ir.annexonbio.com/news-releases/news-release-details/annexon-announces-completion-enrollment-pivotal-phase-3-archer/   
[6] New Hope for People Living with a Disease Once Deemed Untreatable: Belite Bio Announces Positive Topline Results from the Pivotal Global, Phase 3 DRAGON Trial of Tinlarebant in Adolescents with Stargardt Disease https://investors.belitebio.com/news-releases/news-release-details/new-hope-people-living-disease-once-deemed-untreatable-belite 
[7] Sabbah, H. N., Alder, N. N., Sparagna, G. C., Bruce, J. E., Stauffer, B. L., Chao, L. H., Pitceathly, R. D., Maack, C., & Marcinek, D. J. (2025). Contemporary insights into elamipretide’s mitochondrial mechanism of action and therapeutic effects. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 187, 118056. https://doi.org/10.1016/j.biopha.2025.118056
[8] https://www.jnjmedicalconnect.com/products/jnj-81201887/medical-content/parasol-phase-2-clinical-trial  
[9] https://ir.ocugen.com/news-releases/news-release-details/ocugen-announces-topline-12-month-data-phase-2-armada-clinical/ 
[10] https://www.sanofi.com/en/media-room/press-releases/2025/2025-07-16-05-00-00-3116124
[11] Rathi, S., Didangelos, A., Pisarenka, S., Green, R., Zafeiri, S., Emery-Billcliff, P., Patel, N., Whalley, P., Zamiri, P., Tilakaratna, V., Szula, E., Hasan, R., Munye, M. M., Unwin, R. D., Bishop, P. N., Keefe, D., & Clark, S. J. (2025). CTx001 for Geographic Atrophy: A Gene Therapy Expressing Soluble, Truncated Complement Receptor 1 (Mini-CR1). Ophthalmology Science, 6(1), 100980. https://doi.org/10.1016/j.xops.2025.100980 
[12] https://newsroom.regeneron.com/news-releases/news-release-details/regeneron-announces-positive-results-phase-3-trial-generalized
[13] https://www.adarx.com/adarx-pharmaceuticals-announces-positive-interim-phase-1-clinical-data-for-its-novel-sirna-targeting-complement-factor-b-cfb/
[14] Riemann C. OpRegen retinal pigment epithelium (RPE) cell therapy for patients with geographic atrophy (GA): month 36 results from the phase 1/2a trial. Presented at: Clinical Trials at the Summit; June 21, 2025; Las Vegas.
[15] Avery RL. AVD-104 for geographic atrophy secondary to age-related macular degeneration: A review of the phase 2a SIGLEC findings and an overview of the SIGLEC phase 2b study. Presented at: Macula Society meeting; February 13, 2025; Charolette Harbor, Florida.