Abstract
Purpose :
Lampalizumab failed to slow lesion growth in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) in recent studies. We therefore evaluated the effect of lampalizumab on ocular complement activity and explored the broader role of complement activity in GA progression by measuring complement in patient aqueous humor (AH).
Methods :
Two Phase 3 double-masked randomized controlled clinical trials, Chroma (NCT02247479) and Spectri (NCT02247531), enrolled participants aged ≥50 years with bilateral GA and no evidence of prior or active neovascular AMD. Participants were randomized to receive 10mg of intravitreous lampalizumab or sham every 4 (Q4W) or 6 (Q6W) weeks, over 96 weeks. Baseline and week 24 AH samples from 100 patients across treatment arms were measured for both full-length complement protein 3 (C3), complement factor B (CFB), and complement protein 4 (C4), as well as complement activation products C3b/iC3b/C3c, Bb, and C4b/C4c using custom Quanterix Simoa immunoassays. The effect of lampalizumab on complement activity, defined as the cleaved-to-full-length ratio, was compared to sham control using a two-sample t-test of the % change. Correlations between complement activity and lesion size and growth rate were determined using Spearman’s correlation.
Results :
Lampalizumab-treated patients (pooled Q4W/Q6W) demonstrated a 40% reduction in ocular CFB activation compared to sham-treated patients (8% increase, p < 0.001). Similar reductions in CFB activation between Q4W and Q6W treated patients suggests maximum target occupancy by lampalizumab was achieved. Despite this effect, no change in either C3 or C4 activation was observed. Additionally, no meaningful correlations between complement protein levels or activity and GA lesion size or growth rate were observed.
Conclusions :
While analysis of AH from patients treated with lampalizumab showed clear inhibition of the alternative complement pathway, no evidence of C3 inhibition and no compensatory activation of the classical pathway was observed, suggesting that an alternative approach may be more effective in inhibiting downstream complement activity. Additionally, ocular complement was found to be neither prognostic for GA lesion growth nor correlated with GA lesion size, prompting the need for further investigation into the role of complement in GA progression.
This is a 2020 ARVO Annual Meeting abstract.