Although the response of treatment naïve nAMD in the TENAYA and LUCERNE studies was shown to have excellent results with extended fixed treatment regimens of every-8-week to every-16-weeks [4], the response of anti-VEGF resistant nAMD eyes to faricimab has not been well reported. In this series there was a significant improvement in the main endpoint of anatomic resolution of subretinal and intraretinal fluid in 69% of eyes, but 31% of eyes did not show a beneficial effect of faricimab anatomically at 6 months over previous anti-VEGF injections. Unlike in treatment naïve eyes there was no evidence of increased interval between anti-VEGF injections in this short-term study. However, a completely dry macula was required in this study before extension of the injection interval, whereas interval extension was allowed in Tenaya and Lucerne if there was no increase ≥ 50 µm in CRT, no decrease ≥ 5 letters in best corrected VA, and no new macular hemorrhage. This study had only small numbers, but no difference was detected between the subgroups of typical nAMD or PCV.
There is one previous paper of case control study that compared effects of 3 injections of faricimab to those of aflibercept in treatment-resistant exudative AMD subjects previously treated with intravitreal aflibercept [6]. They reported no difference in vision but just decrease in central retinal thickness. Different from our study, they did neither require resolution of edema or subretinal fluid, nor evaluate to determine PCV or typical nAMD. Our study did not show difference in central macular thickness.
Aflibercept has been shown to have significantly more effect on the anatomic results of exudative AMD than ranibizumab [7]. Aflibercept is a full-length antibody with a normal Fc component, whereas ranibizumab is an antibody fragment without an Fc component. In vitro studies have shown that agents with a Fc component are actively transported into the subretinal space, where agents without a Fc component move into the subretinal space through passive diffusion. Faricimab has a modified Fc fragment which limits attachment to receptors to allow more prolonged drug levels in the eye, decreased systemic levels, and decreased inflammation. We speculate that the effect of faricimab is affected by the alterations in the Fc component of the drug, which may affect active transport of faricimab by the RPE into the sub-RPE space.
This study has several limitations. This is a retrospective study, but the case series was consecutive. The number of subjects is small, but because of only recent FDA approval the response in anti-VEGF resistant eyes to faricimab is limited, and this case series provides useful preliminary data. The follow-up is limited at 6 months, but this includes a response to at least 3 faricimab injections. Anti-VEGF resistance is more common in PCV, and this is the only study which evaluates the response to faricimab in anti-VEGF resistant eyes with the diagnosis of PCV or typical nAMD confirmed on ICG angiography. Further investigations including longer follow-up and larger numbers are needed.