A Review of Completed and Ongoing Complement Inhibitor Trials for Geographic Atrophy Secondary to Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among older adults in the Western world. While therapies exist for patients with exudative AMD, there are currently no approved therapies for non-exudative AMD and its advanced form of geographic atrophy (GA). The discovery of genetic variants in complement protein loci with increased susceptibility to AMD has led to the investigation of the role of complement inhibition in AMD with a focus on GA. Here, we review completed and ongoing clinical trials evaluating the safety and efficacy of these studies. Overall, complement inhibition in GA has yielded mixed results. The inhibition of complement factor D has failed pivotal phase 3 trials. Studies of C3 and C5 inhibition meeting their primary endpoint are limited by high rates of discontinuation and withdrawal in the treatment arm and higher risks of conversion to exudative AMD. Studies evaluating other complement members (CFB, CFH, CFI and inhibitors of membrane attack complex—CD59) are ongoing and could offer other viable strategies.

Early Diagnostic Ability of Human Complement Factor B in Pancreatic Cancer Is Partly Linked to Its Potential Tumor-Promoting Role

“…However, the molecular mechanism underlying CFB’s role in a tumor microenvironment where CFB’s activity appears to be coupled to both inflammation and tumorigenesis remains to be elucidated. , Given that the local production of CFB (e.g., in pancreatic exocrine cells) is well known, , it would be plausible to explore the signaling pathway that promotes CFB secretion during the early stage of tumorigenesis in the pancreatic ductal endothelium. Because CA19-9 was recently proposed to be a potential anticancer drug target, CFB may also be a potential therapeutic target for PC treatment. , Because CFB is a key factor in the alternative pathway that serves as the first line of defense against infection and inflammation, one can anticipate its multiple roles, including as a biomarker and as a therapeutic target in other diseases (e.g., PC and diseases of the skin, kidney, heart, and eyes). ,− In that regard, a few specific inhibitors of CFB have been developed for the treatment of those diseases, such as glomerulopathy and age-related macular degeneration …”

Cell Death in AMD: The Rationale for Targeting Fas

“…Previously, several approaches have been taken (caspase inhibitors, etc.) with only limited success due to intracellular shunting of the death signal [5,[31][32][33]. An alternative approach is to target the upstream points of the cell death signaling cascade activation.…”

“…Currently, many approaches are being tested, both pre-clinically and in patients, aimed at reducing GA lesion growth. Such approaches target various pathways implicated in AMD pathogenesis, including the complement system, mitochondrial stress, and the visual cycle, among others (reviewed in references [5][6][7]). In this work, we review cell death pathway activation during AMD and propose that targeting the Fas receptor is a novel approach to prevent RPE and photoreceptor cell death in atrophic AMD.…”

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

“…As previously discussed, CFH polymorphisms are strongly associated with AMD. Recombinant CFH molecules are assumed to reduce the expansion of disease in dry AMD caused by CFH gene loss of function [ 150 ]. The safety and tolerability of a single dose of intravitreally administered GEM103 (Gemini Therapeutics), a full-length recombinant CFH, is now being evaluated in the Phase 2a ReGAtta study in dry AMD (NCT04643886).…”