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Complement Inhibition in Geographic Atrophy: Clinical Evidence for Pegcetacoplan and Avacincaptad Pegol
Gloriana Orozco Loaiza1, Maria Jimena Alfaro Guerra1, Adrián Murillo Sotela1
1Faculty of Medicine, Universidad de Costa Rica, San José, CRI.
Insights
Geographic atrophy (GA), an advanced form of age-related macular degeneration (AMD), involves complement cascade dysregulation. Complement inhibitors like pegcetacoplan and avacincaptad pegol slow GA lesion growth but show limited visual acuity improvement.
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Geographic atrophy (GA) is the advanced stage of non-neovascular age-related macular degeneration (AMD), causing irreversible vision loss.
- Complement cascade dysregulation is a key factor in GA pathophysiology.
- Current FDA-approved therapies target complement inhibition.
Purpose of the Study:
- To provide an overview of geographic atrophy (GA).
- To emphasize the role of the complement cascade in GA pathophysiology.
- To discuss the clinical relevance of complement inhibitors in managing GA.
Main Methods:
- This is a narrative review.
- Key clinical trials (OAKS, DERBY, GALE, GATHER1, GATHER2) were analyzed.
- Pathophysiology and therapeutic outcomes were synthesized.
Main Results:
- Pegcetacoplan (C3 inhibitor) and avacincaptad pegol (C5 inhibitor) significantly reduced GA lesion area by 16-28% compared to sham treatments.
- While structural outcomes were favorable, improvements in best-corrected visual acuity (BCVA) and low-luminance visual acuity (LLVA) were limited.
- Concerns regarding the side effect profiles of these therapies persist.
Conclusions:
- Complement inhibitors represent a significant advancement in GA management by reducing lesion progression.
- Further research is needed to optimize functional outcomes and address safety concerns.
- Understanding complement cascade's role is crucial for developing future GA therapies.
Abstract:
Geographic atrophy (GA) represents the advanced form of non-neovascular age-related macular degeneration (AMD) and is associated with progressive and irreversible vision loss. Evidence has implicated the dysregulation of the complement cascade as a pivotal factor in GA pathophysiology, leading to the development of complement inhibition therapies. Pegcetacoplan, a C3 inhibitor, and avacincaptad pegol, a C5 inhibitor, are currently the only therapies approved by the Food and Drug Administration (FDA) for GA secondary to AMD. Major clinical trials, including OAKS, DERBY, GALE, GATHER1, and GATHER2, have demonstrated a statistically significant reduction in GA lesion area, with reductions of approximately 16-22% for pegcetacoplan and 14-28% for avacincaptad pegol compared with sham. Despite favorable structural outcomes, functional endpoints like best-corrected visual acuity (BCVA) and low-luminance visual acuity (LLVA) have shown limited improvement, and concerns remain regarding their side effect profile. This narrative review provides an overview of GA, emphasizing its pathophysiology and the role of the complement cascade, and discusses the clinical relevance of complement inhibitors in the current management of the disease.
