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BackgroundData comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking.MethodsFifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections.ResultsFollowing the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL.ConclusionsThere are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF.Trial registration numberNCT02118831.

After monthly intravitreal injections, the systemic exposures of aflibercept, bevacizumab, and ranibizumab were distinct and correlated with different reductions in plasma free–vascular endothelial growth factor, which could provide biologic plausibility for potential differences in systemic adverse events.

The observed anatomic (by ophthalmic examination, OCT, and/or fluorescence angiography) and visual acuity improvements and lack of serious adverse side effects after intravitreal bevacizumab injection demonstrates, in principle, the potential of bevacizumab for the treatment of ME in this setting.

With the identification of vascular endothelial growth factor (VEGF) and the confirmation of its pathophysiologic link to retinal and choroidal angiogenesis, numerous agents have been designed to inhibit its activity. It is noteworthy that anatomic and visual benefits have been associated with the use of anti-VEGF agents such as pegaptanib (Macugen) and to a greater extent, ranibizumab (Lucentis) and bevacizumab (Avastin), particularly in the management of neovascular age-related macular degeneration (AMD). Clinical trials and case series have confirmed the utility of these agents. However, shortcomings of the current drugs such as short half-life, intraocular dosing, limited effectiveness in some patients, and potential systemic side effects continue to drive the development of new agents. In this article, we review current anti-VEGF therapies and discuss future developments.

To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD).Design: Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials.Participants: Eligible patients were aged !50 years. Patients in Proxima A had bilateral GA without choroidal neovascularization (CNV) in either eye (N ¼ 295). Patients in Proxima B had GA without CNV in the study eye and CNVAEGA in the fellow eye (fellow eye CNV cohort, n ¼ 168) or GA without CNV in the study eye, no CNV/GA in the fellow eye (fellow eye intermediate AMD cohort, n ¼ 32).Methods: Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics.Main Outcome Measures: Prespecified end points included change in GA area from baseline, bestcorrected visual acuity (BCVA) score assessed by Early Treatment Diabetic Retinopathy Study (ETDRS), and visual acuity under low-luminance (LLVA).Results: At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mm 2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm 2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm 2 in the fellow eye intermediate AMD cohort (Proxima B). Progression of GA was greater in patients with baseline nonsubfoveal (vs. subfoveal) GA lesions and tended to increase as baseline low-luminance deficit increased (all patients). Conversion to GA or CNV in the fellow eye occurred in 30% and 6.7% of participants, respectively, in the Proxima B intermediate AMD cohort at month 12. Adjusted mean (standard error) changes in BCVA and LLVA (ETDRS letters) in the study eye from baseline to 24 months were À13.88 (1.40) and À7.64 (1.20) in Proxima A, À9.49 (1.29) and À7.57 (1.26) in Proxima B fellow eye CNV cohort, and À11.48 (3.39) and À8.37 (3.02) in Proxima B fellow eye intermediate AMD cohort, respectively.Conclusions: The prospective Proxima A and B studies highlight the severe functional impact of GA and the rapid rate of GA lesion progression over a 2-year period, including in patients with unilateral GA at baseline.

These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.