Dry vs Wet Age-Related Macular Degeneration

Dry vs Wet Age-Related Macular Degeneration: Mechanisms, Progression, and Treatment Landscape (2026 Review)

Abstract

Age-related Macular Degeneration (AMD) remains a leading cause of irreversible vision loss in individuals over the age of 50. This review delineates the pathophysiological distinctions between the non-exudative (dry) and exudative (wet) forms of the disease. Dry AMD is characterized by the progressive accumulation of extracellular deposits known as drusen and the eventual atrophy of the retinal pigment epithelium (RPE) and photoreceptors, termed geographic atrophy (GA). Conversely, wet AMD involves pathological choroidal neovascularization (CNV), where leaky vessels cause rapid fluid accumulation and scarring. While the treatment landscape for wet AMD has been revolutionized by anti-vascular endothelial growth factor (VEGF) therapies, dry AMD treatment has historically been limited to nutritional supplementation. However, the recent clinical validation of complement inhibitors has marked a paradigm shift in managing GA. This review synthesizes current understanding of the complement cascade, oxidative stress, and lipid metabolism in AMD pathogenesis, evaluates current clinical interventions, and explores emerging gene and cell-based therapies that define the 2026 clinical horizon.

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Introduction

Age-related Macular Degeneration (AMD) is a complex, multifactorial disease of the central retina. As the global population ages, the prevalence of AMD is projected to increase significantly, placing a substantial burden on healthcare systems (1). The disease is broadly categorized into two clinical phenotypes: the "dry" (non-exudative) form, which accounts for approximately 80–90% of cases, and the "wet" (exudative) form, which, though less common, is responsible for the majority of legal blindness if left untreated (2).

The transition from healthy aging to AMD involves a breakdown in the homeostatic relationship between the neurosensory retina, the retinal pigment epithelium (RPE), Bruch’s membrane, and the underlying choriocapillaris. While both forms share common genetic and environmental risk factors—most notably polymorphisms in the complement factor H (CFH) gene and cigarette smoking—their clinical trajectories and molecular drivers diverge significantly as the disease reaches advanced stages (1,3).

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Mechanistic Sections

Pathophysiology of Dry AMD: Drusenogenesis and Geographic Atrophy

The hallmark of early dry AMD is the presence of drusen—yellowish deposits of lipids, proteins, and minerals located between the RPE and Bruch’s membrane (4).

• Lipid Metabolism and Oxidative Stress: The RPE is responsible for phagocytosing the lipid-rich outer segments of photoreceptors. With age, this process becomes less efficient, leading to the accumulation of lipofuscin within RPE cells and the extracellular deposition of debris. Oxidative stress, fueled by high oxygen consumption and light exposure, exacerbates RPE dysfunction, creating a pro-inflammatory environment (5).

• The Complement Cascade: Genetic studies have firmly established the role of the innate immune system in dry AMD. Overactivation of the alternative complement pathway leads to chronic inflammation and tissue damage. Specifically, the formation of the membrane attack complex (MAC) on RPE cell membranes results in cell lysis and death (6).

• Geographic Atrophy (GA): In advanced dry AMD, the loss of RPE cells becomes confluent. This "geographic" loss leads to the secondary death of overlying photoreceptors and the underlying choriocapillaris, resulting in permanent blind spots (scotomas) in the central vision (4,6).

Pathophysiology of Wet AMD: Choroidal Neovascularization (CNV)

Wet AMD is defined by the growth of abnormal blood vessels from the choroid into the sub-RPE or sub-retinal space.

• Angiogenic Signaling: The primary driver of this process is vascular endothelial growth factor (VEGF). Under conditions of hypoxia or inflammation—often triggered by the thickening of Bruch’s membrane in dry AMD—the retina upregulates VEGF to stimulate new vessel growth (7).

• Vascular Leakage and Fibrosis: Unlike healthy vessels, these neovascular membranes are fragile and highly permeable. They leak serum, lipids, and blood into the retinal layers, leading to macular edema. If the exudation persists, the resulting inflammatory response leads to the formation of a disciform scar, which permanently destroys the foveal architecture (2,7).

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Clinical Research and Treatment Landscape

Pharmacological Management of Wet AMD

The standard of care for wet AMD remains the periodic intravitreal injection of anti-VEGF agents.

• Ranibizumab and Aflibercept: These agents revolutionized AMD care by transitioning the goal from "slowing vision loss" to "improving visual acuity" (8).

• Next-Generation Agents: As of 2026, longer-acting agents such as faricimab, which targets both VEGF and angiopoietin-2 (Ang-2), have gained widespread use. By stabilizing the vasculature more effectively than VEGF inhibition alone, these dual-pathway inhibitors have increased the interval between injections for many patients (9).

• High-Dose Aflibercept: Clinical trials (e.g., PULSAR) have demonstrated that higher doses (8 mg) can extend the treatment effect, reducing the overall injection burden while maintaining safety profiles comparable to standard doses (10).

Therapeutic Advances in Dry AMD: Complement Inhibition

The landscape shifted with the approval of pegcetacoplan and avacincaptad pegol. Pegcetacoplan targets C3, the central hub of the complement cascade, while avacincaptad pegol inhibits C5.

• Pegcetacoplan (OAKS, DERBY, and GALE): Phase 3 trials and the GALE extension study have demonstrated that monthly or every-other-month injections significantly slow GA lesion expansion. By month 36, continuous treatment showed an anatomical benefit of up to 42% reduction in GA growth in nonsubfoveal patients compared to projected sham (11,12).

• Avacincaptad Pegol (GATHER2): Long-term data (3.5 years) released in late 2025 showed a 37–40% reduction in GA growth compared to projected sham. Notably, earlier intervention led to greater preservation of retinal tissue (13,14).

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Comparative Safety and Real-World Evidence (2026)

Real-world evidence (RWE) from 2025–2026 has provided critical insights into the side-effect profiles of these agents when used in clinical practice.

Table 1: 2026 Real-World Safety Comparison

• Exudative Conversion: RWE highlights that patients with a prior history of wet AMD or non-exudative macular neovascularization (MNV) at baseline have a significantly higher risk (up to 70%) of developing fluid during pegcetacoplan treatment (15).

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Emerging Research Directions

Gene Therapy

To address the burden of frequent injections, research is moving toward "one-and-done" gene therapy.

• OCU410 (AAV5-RORA): Preliminary 12-month Phase 2 data (ArMaDa trial) reported in January 2026 showed a 46% reduction in GA lesion growth compared to control. OCU410 targets multiple pathways, including oxidative stress and lipid metabolism (17,18).

• CTx001: An AAV-based therapy delivering Complement Receptor 1 (CR1) to modulate complement pathways locally. It received FDA Fast Track designation in early 2026 (19).

Next-Generation Complement Targets

• ANX007 (Vonaprument): A C1q inhibitor focusing on synapse protection. Unlike C3/C5 inhibitors, the pivotal Phase 3 ARCHER II trial (topline data expected late 2026) uses prevention of 15-letter vision loss as its primary endpoint, aiming for functional rather than just anatomical success (20,21).

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Conclusion

The dichotomy between dry and wet AMD is increasingly understood not as two separate diseases, but as different clinical outcomes of a shared degenerative process. While anti-VEGF therapy remains the cornerstone for wet AMD, the clinical validation of complement inhibitors has provided a long-awaited pathway for dry AMD. The 2026 clinical landscape highlights a transition toward functional endpoints—such as the preservation of visual acuity—and the use of long-acting gene therapies to maintain visual function over the patient’s lifetime.

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References

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14. Astellas Pharma. IZERVAY™ Showed Increased Benefit and Consistent Long-Term Safety. 2025. https://newsroom.astellas.com/2025-10-19-IZERVAY-TM-avacincaptad-pegol-intravitreal-solution-Showed-Increased-Benefit-in-Reducing-Geographic-Atrophy-Progression-Over-Time-and-Consistent-Long-Term-Safety

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17. Ocugen, Inc. Ocugen Announces Positive Preliminary Phase 2 Data from OCU410. 2026. https://ir.ocugen.com/news-releases/news-release-details/ocugen-announces-positive-preliminary-phase-2-data-ocu410/

18. CGTlive. Ocugen Posts Positive Preliminary Phase 2 ArMaDa Trial Data of OCU410. 2026. https://www.cgtlive.com/view/ocugen-positive-preliminary-phase-2-armada-trial-data-ocu410

19. Ophthalmology Times. FDA grants Fast Track Designation to CTx001 for GA. 2026. https://www.ophthalmologytimes.com/view/fda-grants-fast-track-designation-to-complement-therapeutics-ctx001-for-geographic-atrophy

20. Annexon, Inc. Annexon Presents Phase 2 Vision Preservation Data with ANX007. 2024. https://ir.annexonbio.com/news-releases/news-release-details/annexon-presents-phase-2-vision-preservation-data-anx007-dry-amd/

21. Ophthalmology Times. Annexon completes enrollment in phase 3 ARCHER II trial of vonaprument (ANX007). 2025. https://www.ophthalmologytimes.com/view/annexon-completes-enrollment-in-phase-3-archer-ii-trial-of-vonaprument-for-geographic-atrophy

This article is for educational purposes only and reflects current scientific literature at the time of writing.

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