Complement Inhibitors for Advanced Dry Age-Related Macular Degeneration (Geographic Atrophy): Some Light at the End of the Tunnel?

Abstract

Geographic atrophy (GA) affects around 5 million individuals worldwide. Genome-wide, histopathologic, in vitro and animal studies have implicated the activation of the complement system and chronic local inflammation in the pathogenesis of GA. Recently, clinical trials have demonstrated that an intravitreal injection of pegcetacoplan, a C3 inhibitor, and avacincaptad pegol, a C5 inhibitor, both statistically significantly reduce the growth of GA up to 20% in a dose-dependent fashion. Furthermore, the protective effect of both pegcetacoplan and avacincaptad appear to increase with time. However, despite these anatomic outcomes, visual function has not improved as these drugs appear to only slow down the degenerative process. Unexpected adverse events included conversion to exudative NV-AMD with both drugs. Occlusive retinal vasculitis and anterior ischemic optic neuropathy have been reported in pegcetacoplan-treated eyes.

PolySialic Acid Nanoparticles Actuate Complement-Factor-H-Mediated Inhibition of the Alternative Complement Pathway: A Safer Potential Therapy for Age-Related Macular Degeneration

“…In a C3 knockout mice strain, amyloid beta accumulation on the Bruch’s membrane was reported, along with increased levels of retinal TNF-alpha and calcitonin, pointing to an important role of C3 in maintaining retinal homeostasis [ 47 ]. Spontaneous inflammation seen in C3 knockout mice may play a role in the pathogenesis of retinal vasculitis seen clinically in patients receiving intravitreal injections of a profound C3 depleter pegcetacoplan [ 20 ].…”

The Association Between Metformin Use and New-Onset ICD Coding of Geographic Atrophy

“…Additionally, patients treated with pegcetacoplan and avacincaptad pegol appear to be at a higher risk of developing wet AMD and require an intense treatment regimen of monthly injections, which may be a burden to patients and carries a risk of endophthalmitis and retinal inflammation. 33 , 36 In fact, the American Society of Retina Specialists Research and Safety in Therapeutics Committee has recently reported cases of retinal vasculitis in 14 eyes of 13 patients, all developing following their first injection of pegcetacoplan. 37 The poor functional data and drastic side effect profile for these recently approved therapeutics underscore the ongoing shortcomings in the treatment of GA.…”

Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System

“…Occurrences of CNV were also noted in 11%, 8%, and 2% of patients in the OAKS trial, and in 13%, 6%, and 4% of patients in the DERBY trial, corresponding to those treated monthly, two-monthly, and sham-treated, respectively, at the 24-month mark [359]. Another observable side effect in the FILLY trial was the occurrence of endophthalmitis following injection, with 2.3% of eyes in the monthly-injected subgroup experiencing this serious ocular infection [355], while the rates of endophthalmitis were lower in the DERBY and OAKS trials [360].…”

“…Along with avacincaptad pegol, also eculizumab and tesidolumab were designed as C5 inhibitors and tested for the management of GA in dedicated clinical trials. Eculizumab, a murine humanized monoclonal antibody inhibiting C5 [360], underwent evaluation in the COMPLETE study, a prospective, double-masked, randomized phase 2 clinical trial with 30 GA patients. Unfortunately, it reported a lack of effectiveness in reducing GA growth [368].…”