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.

Keywords: C3; C5; age-related macular degeneration; avacincaptad; cRORA; complement inhibitors; geographic atrophy; iRORA; pegcetacoplan.

Figure 1

Complete retinal pigment epithelium outer retinal atrophy (cRORA). Foveal cut of an SD-OCT (Heidelberg Spectralis) image of an 89-year-old woman with a visual acuity of 20/400. Both the areas of hypertransmission and RPE (area between the red arrows) match and measure 1546 µm.

Figure 2

Incomplete retinal pigment epithelium outer retinal atrophy (iRORA). Foveal cut of an SD-OCT (Heidelberg Spectralis) image of an 83-year-old woman with a visual acuity of 20/80. The arrows point to the presence of a hyporeflective wedge in the Henle fiber layer (HFL). The star is adjacent to an area of choroidal hypertransmission <250 µm.