Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) remains a leading cause of irreversible central vision loss, and complement dysregulation has long been implicated in its pathogenesis. In 2023, the US FDA approved the first two GA therapies, both complement inhibitors. Avacincaptad pegol (ACP) is a pegylated RNA aptamer targeting complement C5. GATHER2 was a phase 3, multicentre, double-masked, sham-controlled trial of 448 patients with non-centre-point-involving GA across 20 countries. Patients were randomised 1:1 to monthly ACP 2mg or sham for year 1. At month 12, ACP-treated eyes were re-randomised to continue every month (EM) or switch to every other month (EOM). The prespecified year 2 primary endpoint was met for ACP EM versus sham, with a difference in GA growth of 0.724mm² over 2 years (95% CI 0.133–1.315; p=0.0165); a 14% reduction. Every-other-month dosing produced a numerically larger 19% reduction (difference 0.976mm², nominal p=0.0015), and a piecewise analysis showed the treatment effect emerged by month 6 and more than doubled between years 1 and 2. However, no significant differences were seen in mean change in best corrected visual acuity (BCVA) (-7.31 vs -6.48 ETDRS letters), low-luminance BCVA, or in the prespecified time-to-event analysis of persistent 15-letter vision loss (HR 0.90; p=0.64); a notable shift from the post-hoc year 1 signal (HR 0.41). The authors argue structural endpoints are more reproducible than functional ones over this timeframe, although the persistent structure-function disconnect remains the central question in GA therapeutics. Safety was reassuring: no cases of retinal vasculitis, ischaemic optic neuropathy, or serious intraocular inflammation occurred, and choroidal neovascularisation rates (11.6% ACP vs 9.0% sham) were consistent with year 1. The findings support sustained anatomical benefit with both regimens, with a less frequent dosing schedule offering an attractive treatment burden reduction. Whether slowing lesion growth translates into preserved vision over longer follow-up remains to be established.
