Investigators evaluated the potential benefits and ongoing concerns regarding the efficacy, safety, and regulatory decisions of complement inhibition therapy in geographic atrophy.
While treatments such as pegcetacoplan and avacincaptad pegol have shown promise in slowing disease progression, wrote Huixun Jia, PhD, of the Department of Ophthalmology at Shanghai General Hospital at the Shanghai Jiao Tong University School of Medicine, and Xiaodong Sun, MD, PhD, of the National Clinical Research Center for Eye Diseases, both in Shanghai, China, uncertainties remain about their functional benefits and long-term risks.
The phase III DERBY (ClinicalTrials.gov identifier NCT03525600) and OAKS (ClinicalTrials.gov identifier NCT03525613) trials demonstrated a relative reduction in geographic atrophy (GA) lesion growth by 16% to 22% over 24 months, according to the JAMA Ophthalmology Viewpoint article. Absolute mean reductions in GA area were 0.90 mm² (OAKS) and 0.75 mm² (DERBY) compared with sham treatments. Avacincaptad pegol showed a 27% and 14% reduction in GA growth over 12 months, which supported the therapeutic potential of complement inhibition.
However, the investigators described, the findings come with methodological concerns. The primary endpoints of the trials—which measured the mean change in GA lesion area—included both existing lesion expansion and the formation of new lesions. The lack of differentiation between these processes raised questions about whether complement inhibition primarily slows lesion enlargement, prevents new lesion formation, or both. More broadly, the primary endpoints were “anatomical, rather than functional,” the study authors suggested.
They also noted the risks that frequent intravitreal injections pose. Clinical trials have reported a 12% incidence of neovascularization in treated patients compared with lower rates in placebo groups. While trial data did not indicate cases of occlusive vasculitis, real-world postmarketing data identified cases at a rate of 1 per 10,000 injections, which led to updated safety warnings for pegcetacoplan. Avacincaptad pegol lists active intraocular inflammation as a potential adverse effect but does not currently include warnings about occlusive vasculitis or vascular occlusion.
Despite the promising data, concerns also persist regarding regulatory approvals and clinical adoption. The U.S. Food and Drug Administration approved pegcetacoplan in February 2023, citing an urgent need for GA treatments. However, the European Medicines Agency (EMA) rejected its marketing authorization in September 2024 for a lack of clear functional benefits and safety risks associated with frequent intravitreal injections. The EMA’s decision followed an initial negative opinion in January 2024, which was reaffirmed after a reexamination in June.
Astellas withdrew its application for avacincaptad pegol in October 2024, following discussions with the EMA.
The investigators noted that a key limitation in current GA therapies is the lack of measurable functional improvement. Unlike anti-VEGF therapies, which show clear gains in visual acuity and disease stability, complement inhibition has not demonstrated statistically significant differences in predefined secondary visual function endpoints. While some post hoc analyses have suggested possible benefits, the findings remain exploratory and require further validation.
“Physicians still should discuss these drugs with patients with GA,” the study authors concluded, “including informing them about drugs denied in Europe or pending approval elsewhere, such as Australia or Asia.”
Moving forward, the investigators emphasized that research should explore alternative therapeutic targets beyond complement inhibition. Potential avenues could include mitochondrial dysfunction, hypoxia-related mechanisms, toxic byproducts of the visual cycle, and inflammatory pathways. They should also “better integrate anatomical changes with functional outcomes to make this hope a reality for patients,” the study authors concluded.
No conflicts of interest were reported.