“Age-related macular degeneration (AMD) is a leading cause of blindness in the aging population worldwide,” wrote Thomas Ciulla, MD, MBA, and colleagues in Expert Opinion on Pharmacotherapy. “Therapeutic options for AMD have traditionally been limited to treatment of macular neovascularization (MNV) in exudative AMD. However, modulation of the complement system, a component of the innate immune system, has recently emerged as a promising therapeutic approach for slowing the progression of geographic atrophy (GA) in AMD.”
The investigators reviewed the “current understanding of the complement system, its role in AMD, and the various complement-targeting therapies in development for the treatment of GA, including monoclonal antibodies, aptamers, protein analogs, and gene therapies.”
Complement Inhibition & Other Approaches
The pathophysiology of AMD involves oxidative stress, inflammation, and dysregulation of the complement system, a part of the innate immune system. Dysregulation of the complement system is strongly implicated in AMD, especially in GA. Recent advancements in AMD treatment have focused on complement inhibition.
The complement system is a complex network of proteins involved in immune response and includes three activation pathways: classical, lectin, and alternative. The alternative pathway, constitutively active, is a key target for AMD therapies. Genetic variations in complement-related genes, such as complement factor H (CFH) and complement factor I (CFI), have been associated with an increased risk for AMD, leading to local inflammation and retinal pigment epithelium (RPE) damage in the macula.
Several complement inhibitors have shown promise in clinical trials. Pegcetacoplan is an intravitreal C3 inhibitor. In a Phase 2 trial (FILLY), pegcetacoplan significantly slowed GA progression compared with a sham procedure, without a substantial risk for MNV. Avacincaptad pegol, an aptamer-based C5 inhibitor, demonstrated similar success in a Phase 2b trial (GATHER2). It significantly reduced GA progression without a significant risk for MNV conversion.
Gene therapy is another promising approach. HMR59 utilizes an adeno-associated viral vector to deliver a gene-encoding CD59, a membrane attack complex (MAC) inhibitor, to the retina. By preventing MAC formation, HMR59 aims to protect RPE cells and photoreceptors from complement-mediated damage. Preclinical studies showed its potential in reducing complement activation and preserving retinal structure and function.
“Most Viable Known Approach” to Slowing GA Progression
Despite these advances, challenges remain. Frequent intravitreal injections required for some therapies can be burdensome and pose infection risks. Exudative conversion, in which patients with GA who are treated with complement inhibitors may develop MNV, remains a concern. Long-term safety and effectiveness, as well as cost-effectiveness and accessibility, also need further evaluation.
“The complement system has emerged as a promising therapeutic target for AMD and currently represents the most viable known approach to slowing the progression of GA in non-exudative AMD,” wrote Dr. Ciulla and colleagues. “The great success of pegcetacoplan and avacincaptad pegol in large clinical trials is encouraging, and brings hope to millions of patients suffering from progressive vision loss due to AMD. Indeed, the rapid advances in this arena have the potential to revolutionize the approach to AMD and other retinal diseases in much the same way that anti-VEGF therapies have in the course of the past two decades.”