Intraocular Inflammation,Safety Events,and Outcomes After Intravitreal Injection of Ranibizumab,Aflibercept,Brolucizumab,Abicipar Pegol,and Faricimab for nAMD
Restricted accessReview articleFirst published online July, 2025
Intraocular Inflammation,Safety Events,and Outcomes After Intravitreal Injection of Ranibizumab,Aflibercept,Brolucizumab,Abicipar Pegol,and Faricimab for nAMD
Purpose: To compare the rates of intraocular inflammation (IOI) in patients with neovascular age-related macular degeneration (nAMD) after injection of intravitreal (IVT) antivascular endothelial growth factor drugs. Methods: This study included all phase 3 randomized clinical trials of patients with nAMD treated with ranibizumab, aflibercept, brolucizumab, abicipar pegol, or faricimab. The outcomes assessed were the incidence of IOI, retinal artery occlusion (RAO), retinal vasculitis and choroiditis, endophthalmitis, and serious systemic adverse events (AEs) as well as the change in visual acuity (VA) (Early Treatment Diabetic Retinopathy Study letters) and in central retinal thickness (CRT). Results: Abicipar pegol was associated with a higher incidence of IOI than aflibercept, ranibizumab, faricimab, and sham injections, while brolucizumab was associated with a higher rate of IOI than aflibercept, faricimab, and sham injections. Abicipar pegol was also associated with a higher rate of endophthalmitis than aflibercept. Significantly more retinal vasculitis and choroiditis was seen with abicipar pegol and brolucizumab than with ranibizumab and aflibercept, respectively, and RAOs occurred more frequently with abicipar pegol and brolucizumab than with ranibizumab and aflibercept, respectively. There were no differences in the change in VA among the drugs. Treatment with brolucizumab resulted in a greater change in CRT than with abicipar pegol, aflibercept, ranibizumab, and faricimab, while treatment with faricimab resulted in a greater change in CRT than aflibercept and ranibizumab. Faricimab was associated with fewer serious systemic AEs than aflibercept. Conclusions: Abicipar pegol and brolucizumab were associated with a higher incidence of ocular AEs in phase 3 randomized controlled trials. The potential benefits of these drugs should be weighed against the AEs.
BerkowitzSTSternbergPFengXChenQPatelS.Analysis of anti-vascular endothelial growth factor injection claims data in US Medicare Part B beneficiaries from 2012 to 2015. JAMA Ophthalmol. 2019;137(8):921-928. doi:10.1001/jamaophthalmol.2019.1971
2.
GlasserDBParikhRLumFWilliamsGA.Intravitreal anti-vascular endothelial growth factor cost savings achievable with increased bevacizumab reimbursement and use. Ophthalmology. 2020;127(12):1688-1692. doi:10.1016/j.ophtha.2020.06.012
JainACheaSMatsumiyaW, et al. Severe vision loss secondary to retinal arteriolar occlusions after multiple intravitreal brolucizumab administrations. Am J Ophthalmol Case Rep. 2020;18:100687. doi:10.1016/j.ajoc.2020.100687
5.
HaugSJHienDLUludagG, et al. Retinal arterial occlusive vasculitis following intravitreal brolucizumab administration. Am J Ophthalmol Case Rep. 2020;18:100680. doi:10.1016/j.ajoc.2020.100680
6.
BaumalCRSpaideRFVajzovicL, et al. Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. Ophthalmology. 2020;127(10):1345-1359. doi:10.1016/j.ophtha.2020.04.017
7.
WitkinAJHahnPMurrayTG, et al. Occlusive retinal vasculitis following intravitreal brolucizumab. J Vitreoretin Dis. 2020;4(4):269-279. doi:10.1177/2474126420930863
8.
RosenfeldPJBrowningDJ.Is this a 737 MAX moment for brolucizumab?Am J Ophthalmol. 2020;216:A7-A8. doi:10.1016/j.ajo.2020.05.012
HeierJSKhananiAMQuezada RuizC, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022;399(10326):729-740. doi:10.1016/S0140-6736(22)00010-1
11.
FoxtonRHUhlesSGrunerSRevelantFUllmerC.Efficacy of simultaneous VEGF-A/ANG-2 neutralization in suppressing spontaneous choroidal neovascularization. EMBO Mol Med. 2019;11(5):e10204. doi:10.15252/emmm.201810204
12.
SchaeferWRegulaJTBahnerM, et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc Natl Acad Sci U S A. 2011;108(27):11187-11192. doi:10.1073/pnas.1019002108
13.
BrownDMKaiserPKMichelsM, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
14.
BrownDMMichelsMKaiserPK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57-65.e5. doi:10.1016/j.ophtha.2008.10.018
15.
RosenfeldPJBrownDMHeierJS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. doi:10.1056/NEJMoa054481
16.
KhuranaRNKunimotoDYoonYH, et al. Two-year results of the phase 3 randomized controlled study of abicipar in neovascular age-related macular degeneration. Ophthalmology. 2021;128(7):1027-1038. doi:10.1016/j.ophtha.2020.11.017
17.
KunimotoDYoonYHWykoffCC, et al. Efficacy and safety of abicipar in neovascular age-related macular degeneration: 52-week results of phase 3 randomized controlled study. Ophthalmology. 2020;127(10):1331-1344. doi:10.1016/j.ophtha.2020.03.035
18.
DugelPUSinghRPKohA, et al. HAWK and HARRIER: 96-week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2021;128(1):89-99. doi:10.1016/j.ophtha.2020.06.028
19.
DugelPUJaffeGJSallstigP, et al. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: a randomized trial. Ophthalmology. 2017;124(9):1296-1304. doi:10.1016/j.ophtha.2017.03.057
20.
MonesJSrivastavaSKJaffeGJ, et al. Risk of inflammation, retinal vasculitis, and retinal occlusion-related events with brolucizumab: post hoc review of HAWK and HARRIER. Ophthalmology. 2021;128(7):1050-1059. doi:10.1016/j.ophtha.2020.11.011
21.
HeierJSBrownDMChongV, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548. doi:10.1016/j.ophtha.2012.09.006
22.
Schmidt-ErfurthUKaiserPKKorobelnikJF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201. doi:10.1016/j.ophtha.2013.08.011
23.
PierceIAFigueroaMSKotechaA, et al. Faricimab in neovascular age-related macular degeneration: year 2 patient case profiles from the phase 3 TENAYA and LUCERNE trials. Presented at: American Academy of Ophthalmology Annual Meeting; September 30-October 3, 2022; Chicago, IL.
24.
DiasSWeltonNJSuttonAJAdesAE.NICE DSU technical support document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials. National Institute for Health and Care Excellence (NICE); 2014. NICE Decision Support Unit Technical Support Documents.
25.
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; MartinDFMaguireMG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398. doi:10.1016/j.ophtha.2012.03.053
26.
EfthimiouO.Practical guide to the meta-analysis of rare events. Evid Based Ment Health. 2018;21(2):72-76. doi:10.1136/eb-2018-102911
27.
HoganMHKimuraSJThygesonP. Signs and symptoms of uveitis. I. Anterior uveitis. Am J Ophthalmol. 1959;47:155.
28.
JabsDANussenblattRBRosenbaumJT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140(3):509-516.
29.
TabanMBehrensANewcombRL, et al. Acute endophthalmitis following cataract surgery: a systematic review of the literature. Arch Ophthalmol. 2005;123:613-620.
30.
LyallDAMTeyAFootB, et al. Post-intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye. 2012;26:1517-1526.
SharmaAKumarNKuppermannBDBandelloFLoewensteinA.Ophthalmic biosimilars and biologics-role of endotoxins. Eye (Lond). 2020;34(4):614-615. doi:10.1038/s41433-019-0636-3
33.
CallananDKhuranaRNMaturiRK, et al. Impact of modifying abicipar manufacturing process in patients with neovascular age-related macular degeneration: MAPLE study results. Clin Ophthalmol. 2023;17:1367-1384. doi:10.2147/OPTH.S405994
34.
BorrasLGundeTTietzJ, et al. Generic approach for the generation of stable humanized single-chain Fv fragments from rabbit monoclonal antibodies. J Biol Chem. 2010;285(12):9054-9066. doi:10.1074/jbc.M109.072876
35.
NguyenQDDasADoDV, et al. Brolucizumab: evolution through preclinical and clinical studies and the implications for the management of neovascular age-related macular degeneration. Ophthalmology. 2020;127(7):963-976. doi:10.1016/j.ophtha.2019.12.031
36.
BaldoBA.Adverse events to monoclonal antibodies used for cancer therapy: focus on hypersensitivity responses. Oncoimmunology. 2013;2(10):e26333. doi:10.4161/onci.26333
37.
IyerPGPedenMCSunerIJPatelNDubovySRAlbiniTA.Brolucizumab-related retinal vasculitis with exacerbation following ranibizumab retreatment: a clinicopathologic case study. Am J Ophthalmol Case Rep. 2020;20:100989. doi:10.1016/j.ajoc.2020.100989
38.
TadayoniRSararolsLWeissgerberGVermaRClemensAHolzFG.Brolucizumab: a newly developed anti-VEGF molecule for the treatment of neovascular age-related macular degeneration. Ophthalmologica. 2021;244(2):93-101. doi:10.1159/000513048
39.
KearnsJDWassmannPOlgacU, et al. A root cause analysis to identify the mechanistic drivers of immunogenicity against the anti-VEGF biotherapeutic brolucizumab. Sci Transl Med. 2023;15(681):eabq5068. doi:10.1126/scitranslmed.abq5068
40.
TripathiRCBorisuthNSTripathiBJ.Mapping of Fc gamma receptors in the human and porcine eye. Exp Eye Res. 1991;53(5):647-656. doi:10.1016/0014-4835(91)90225-4
41.
TaubitzTSteinbrennerLPTschulakowAVBiesemeierAJulien-SchraermeyerSSchraermeyerU.Effects of intravitreally injected Fc fragment on rat eyes. Graefes Arch Clin Exp Ophthalmol. 2016;254(12):2401-2409. doi:10.1007/s00417-016-3511-y
42.
JulienSBiesemeierATaubitzTSchraermeyerU.Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes. Br J Ophthalmol. 2014;98(6):813-825. doi:10.1136/bjophthalmol-2013-304019
43.
AnandacoomarasamyAKannangaraSBarnsleyL.Cutaneous vasculitis associated with infliximab in the treatment of rheumatoid arthritis. Intern Med J. 2005;35(10):638-640. doi:10.1111/j.1445-5994.2005.00899.x
44.
KimMJKimHOKimHYParkYM.Rituximab-induced vasculitis: a case report and review of the medical published work. J Dermatol. 2009;36(5):284-287. doi:10.1111/j.1346-8138.2009.00639.x
45.
KandulaPKouidesPA.Rituximab-induced leukocytoclastic vasculitis: a case report. Arch Dermatol. 2006;142(2):246-247. doi:10.1001/archderm.142.2.246
46.
D’ArcyCAMannikM.Serum sickness secondary to treatment with the murine-human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum. 2001;44(7):1717-1718. doi:10.1002/1529-0131(200107)44:7<1717::AID-ART299>3.0.CO;2-C
47.
KarleACWrobelMBKoepkeS, et al. Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events. Sci Transl Med. 2023;15(681):eabq5241. doi:10.1126/scitranslmed.abq5241
48.
KorenEDe GrootASJawaV, et al. Clinical validation of the “in silico” prediction of immunogenicity of a human recombinant therapeutic protein. Clin Immunol. 2007;124(1):26-32. doi:10.1016/j.clim.2007.03.544
49.
TangriSMotheBREisenbraunJ, et al. Rationally engineered therapeutic proteins with reduced immunogenicity. J Immunol. 2005;174(6):3187-3196. doi:10.4049/jimmunol.174.6.3187
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