Discussion
endophthalmitis, vitritis
ENDOPHTHALMITIS, DISEASE, VITRITIS
This report presents the results for one of the longest treatment periods with a complement inhibitor of eyes with GA. The data are consistent with the 12-month results previously published, and further support ACP as a potential treatment to reduce GA lesion growth [The visual disability related to GA is often underestimated because BCVA is generally a poor indicator of functional vision in these patients, as the fovea may be spared until late disease stages [While 3 intravitreal dosage regimens were evaluated (1, 2, and 4 mg), the 12- and 18-month reports focused on the 2 and 4 mg study groups. The efficacy outcomes in the 2 and 4 mg ACP study groups were similar, with only an additional 1.9% reduced GA growth with the higher dose. However, the incidence of AEs and AEs related to the injection procedure was higher with the 4 mg dose, most likely due to the increased volume of the injection (200 μl vs. 100 μl) and not necessarily the study drug dosage. Considering the similar efficacy and better safety profile, the 2 mg dose was chosen for a subsequent confirmatory phase 3 study (GATHER2, NCT04435366).Intravitreal ACP over 18 months was generally well tolerated, with no cases of endophthalmitis and only one mild episode of IOI (vitritis) that did not result in study discontinuation. Recent investigations of intravitreal complement inhibitors for GA have revealed increased rates of study eye MNV conversion and, similar to the results at month 12 in GATHER1, increased MNV conversion was observed with 2 mg (11.9%) and 4 mg (15.7%) ACP at 18 months. The results include all investigator-determined MNV subtypes, with or without exudation [The reasons behind the increased rates of MNV in eyes with GA receiving investigational complement inhibitors are not known. Perhaps the clinical efficacy of the study drugs retains healthier vascular endothelial growth factor A (VEGF-A)–producing cells that lead to increased rates of MNV conversion compared to the control group [Despite the rigorously controlled study design, some limitations must be acknowledged. First, the macular imaging included color fundus photography, FAF, fluorescein angiography, and OCT but did not include OCT angiography, which has the novel ability to noninvasively detect the presence of MNV and determine its subtype [In GATHER1, a pivotal phase 2/3 study, there was a consistent reduction in GA growth with monthly intravitreal ACP 2 mg or 4 mg compared to sham through month 18. These findings reinforce the previously published 12-month results and support the ongoing safety and efficacy of complement inhibition in eyes with GA. These results support targeting C5 inhibition within the complement cascade as a promising method to treat GA, and longer-term ACP therapy may potentially provide a cumulative clinical benefit over time. GATHER2, a phase 3 trial, has recently been completed to further investigate the efficacy and safety of ACP 2 mg for GA.