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Purpose: Geographic atrophy (GA) is an age-related neurodegenerative disease involving the loss of photoreceptor cells and visual function. C1q, the initiating molecule of the classical complement cascade, is implicated in neurodegeneration via its unique role in recognition and elimination of synapses on stressed neurons, leading to neuroinflammation and neuronal loss. Inhibition of C1q protects synapses, neurons and retinal function in animal models of photoreceptor damage. In GA, photoreceptor synapse loss occurs prior to the loss of retinal pigmented epithelial (RPE) cells that define lesion area. The ARCHER Ph 2 study was designed to determine the impact of C1q inhibition on disease progression in GA patients.

Methods: ARCHER evaluated the safety and efficacy of ANX007, a humanized Fab antibody against C1q, in patients with GA secondary to AMD. Patients (n=270) were randomized to ANX007 dosed intravitreally at 5 mg monthly (EM), 5 mg every other month (EOM), or their corresponding sham arms through month 12, followed by 6 months off-treatment. The primary endpoint was change in fundus autofluorescence (FAF) GA lesion area, which assesses the presence of RPE cells, but not photoreceptor cells or their function. Importantly, several pre-specified secondary endpoints of visual function were also assessed, including best corrected visual acuity (BCVA).

Results: ANX007 treatment did not significantly slow FAF lesion growth at month 12. However, treatment resulted in consistent, nominally significant, dose- and time-dependent protection of vision, with 5.6% of EM patients (p=0.0021) and 10.9% of EOM patients (p=0.055) experiencing persistent 15-letter loss in BCVA compared to 21.3% of sham patients. The risk for persistent vision loss was reduced 72% in EM (p=0.0006) and 48% in EOM (p=0.064) arms. Treatment effect was independent of baseline characteristics and consistent regardless of foveal center involvement. Following treatment discontinuation, gains in visual function were maintained while the rate of functional decline returned to that of sham. ANX007 was generally well tolerated.

Conclusions: Blockade of classical complement may protect GA patients from loss of clinically-relevant visual function by protecting photoreceptors and synapses from elimination. ARCHER is the first demonstration of visual function protection in a GA clinical study, and represents the potential for neuroprotective effects of C1q inhibition more broadly.