A Distinct Delayed-Onset Intraocular Inflammation Phenotype of Faricimab versus Aflibercept and Ranibizumab: Triangulated Pharmacovigilance Evidence from Databases of US, Europe and Japan

Purpose: Post-marketing reports have associated faricimab, the first intravitreal bispecific antibody, with intraocular inflammation (IOI). Its inflammatory phenotype, temporal pattern and systemic safety relative to established anti-VEGF agents remain unclear. We compared faricimab, aflibercept and ranibizumab across three independent pharmacovigilance databases. Methods: We analysed FAERS reports from Q1 2022 to Q2 2026, with external validation in JADER (PMDA, Japan) and EudraVigilance. Reports were de-duplicated, restricted to primary-suspect reports, and a pre-specified list of 36 non-adverse-event preferred terms (PTs) was excluded. We computed reporting odds ratios (ROR), proportional reporting ratios and Bayesian information components, with Benjamini-Hochberg false discovery rate control. Head-to-head RORs were adjusted for demographic confounders by logistic regression. Time to onset (TTO) was modelled with Weibull distributions. Sensitivity analyses addressed masking and differential market duration. Signals were graded with a pre-specified bidirectional cross-database evidence framework (Confirmed, Consistent, Unconfirmed, Discordant). Results: Faricimab was reported more often for anterior-chamber and vitreal inflammation. Adjusted RORs (comparator versus faricimab, values <1 indicating faricimab excess) were 0.27 (95% CI 0.18-0.40) for iridocyclitis and 0.45 (0.35-0.58) for uveitis versus aflibercept, and 0.13 (0.06-0.24) and 0.12 (0.06-0.20) versus ranibizumab. All four PTs were Confirmed in JADER against both comparators; for iridocyclitis, RORs were 0.048 versus aflibercept and 0.109 versus ranibizumab. Faricimab IOI arose late (median TTO 100 days, IQR 31-182, versus 7 days for both comparators; P = 2.6E-14) and its Weibull onset distribution was markedly flatter (shape 0.81 versus {approx}0.42). In contrast, aflibercept predominated for endophthalmitis-spectrum events and intraocular pressure elevation, and ranibizumab for vitreous haemorrhage, the latter confirmed in JADER. Faricimab showed lower reporting across cardiac, nervous system, vascular and renal system organ classes, confirmed in EudraVigilance. An unadjusted FAERS death signal (ROR 3.16, aflibercept versus faricimab) attenuated after adjustment (aROR {approx}1.8) and was absent in outcome-based JADER analyses. Conclusions: Faricimab exhibits a reproducible, delayed-onset, anterior-predominant IOI phenotype alongside a comparatively favourable systemic safety profile. Clinicians should be aware that faricimab-associated IOI may arise weeks to months after injection. Prospective studies with exposure denominators are needed to quantify absolute risk.