Early Outcome of Aflibercept 8 mg for Neovascular AMD in the Real-world Setting

Abstract

Purpose To investigate the early outcome of intravitreal aflibercept 8 mg in treating neovascular age-related macular degeneration (nAMD) of eyes that either received prior intravitreal anti-VEGF treatment or were treatment-naïve – under real-world conditions.

Methods This is a retrospective study of a total of 83 eyes with nAMD treated with aflibercept 8 mg. 61 of these eyes completed an initial loading phase of 3 monthly intravitreal injections (IVI) and were included in further analyses. Outcome parameters included best-corrected visual acuity (BCVA, logMAR), presence of intraretinal (IRF) and subretinal fluid (SRF), extent of pigment epithelium detachment (PED height, µm) and central subfield retinal thickness (CSRT, µm) in spectral domain optical coherence tomography (SD-OCT). Patients were assessed at the beginning of aflibercept 8 mg treatment and 4 weeks after completing the loading phase. The McNemar test was used to test for changes in distribution of eyes showing IRF and SRF, and the paired t test was performed to test for changes in BCVA, PED height and CSRT.

Results 51 eyes had been previously treated with intravitreal anti-VEGF, while 10 eyes were treatment-naïve. Mean BCVA after completed loading phase was 0.49 ± 0.31 logMAR and did not show changes to baseline BCVA, which was 0.49 ± 0.32 logMAR (p = 0.89). A significant reduction was observed in all disease activity parameters in SD-OCT. The proportion of eyes showing IRF and SRF decreased from 54.1% to 26.2% (p < 0.001) and 65.6% to 24.6% (p < 0.001), respectively. A reduction in PED height from 227.7 ± 114.6 µm at baseline to 191.9 ± 111.4 µm (p < 0.001) and a decrease in CSRT from 375.2 ± 126.2 µm to 308.8 ± 93.7 (p < 0.001) were recorded. Of all eyes (n = 83) that had received at least one IVI aflibercept 8 mg, 5 eyes (6.0%) developed symptomatic, non-infectious intraocular inflammation (IOI), which resolved completely with topical treatment.

Conclusion Our results demonstrate good effectiveness of intravitreal aflibercept 8 mg in the real-world setting, with significant reduction in disease activity parameters in SD-OCT after the loading phase with 3 monthly injections – while BCVA remained stable. While the PULSAR trial only included treatment-naïve eyes, our study underlines the value of aflibercept 8 mg, even for pre-treated eyes that responded insufficiently to previous anti-VEGF treatment. Further studies are needed to evaluate long-term outcome in real-world setting, in order to verify the extended IVI intervals shown in the PULSAR trial.

Zusammenfassung

Zielsetzung Untersuchung des kurzfristigen Effekts von Aflibercept 8 mg intravitreal zur Behandlung der neovaskulären altersbedingten Makuladegeneration (nAMD) bei vorbehandelten und therapienaiven Augen unter Real-World-Bedingungen.

Methoden Dies ist eine retrospektive Studie mit insgesamt 83 Augen, die aufgrund einer nAMD mit intravitrealen Injektionen (IVOM) Aflibercept 8 mg behandelt wurden. 63 Augen vervollständigten einen initialen Upload von 3 monatlichen IVOMs und wurden in weitere Analysen eingeschlossen. Die Outcome-Parameter beinhalteten den bestkorrigierten Visus (BCVA, logMAR), das Vorhandensein von intraretinaler (IRF) und subretinaler Flüssigkeit (SRF), die Höhe der Pigmentepithelabhebung (PED-Höhe, µm) und die zentrale Netzhautdicke (CSRT, µm) in der Spectral Domain-optischen Kohärenz-Tomografie (SD-OCT). Die Patienten wurden zu Beginn des Uploads sowie 4 Wochen nach Upload untersucht. Ein McNemar-Test wurde zur Untersuchung auf Veränderungen des Anteils and Augen verwendet, die IRF und SRF zeigten. Gepaarte t-Tests wurden zur Analyse von BCVA, PED-Höhe und CSRT verwendet.

Ergebnisse 51 Augen waren mit anderen Anti-VEGF-Präparaten vorbehandelt, während 10 Augen therapienaiv waren. Der durchschnittliche Visus nach erfolgtem Upload betrug 0,49 ± 0,31 logMAR und zeigte keine Veränderung zum Baseline-Visus von 0,49 ± 0,32 logMAR (p = 0,89). Es zeigte sich eine signifikante Reduktion aller in der SD-OCT untersuchten Aktivitätsparameter. Der Anteil an Augen mit IRF verringerte sich von 54,1% auf 26,2% (p < 0,001) und der Anteil an Augen mit SRF von 65,6% auf 24,6% (p < 0,001). Zudem war eine Reduktion der PED-Höhe von 227,7 ± 114,6 µm auf 191,9 ± 111,4 µm (p < 0.001) sowie der CSRT von 375,2 ± 126,2 µm auf 308,8 ± 93,7 (p < 0,001) festzustellen. Von allen Augen (n = 83), die bis zur Datenerfassung mindestens eine IVOM Aflibercept 8 mg erhalten hatten, entwickelten 5 Augen (6.0%) eine symptomatische, nicht-infektiöse intraokuläre Inflammation (IOI), die durch topische Therapie komplett regredient war.

Schlussfolgerungen Aflibercept 8 mg zeigt unter Real-World-Bedingungen nach initialem Upload eine gute Wirksamkeit mit stabilem Visus bei der Behandlung der nAMD, sowohl bei vorbehandelten als auch Therapie-naiven Augen. Weitere Studien sind notwendig, um das langfristige Outcome sowie insbesondere verlängerte IVOM-Intervalle unter realen Bedingungen zu untersuchen.

Conclusion Box

Already known:

• Pivotal trial PULSAR has shown promising results with extended injection intervals in a large part of newly diagnosed nAMD eyes treated with aflibercept 8 mg while achieving similar visual gains compared to eyes treated with aflibercept 2 mg.

• Limited data is available confirming effectiveness of aflibercept 8 mg in nAMD under real-world conditions, especially in pre-treated nAMD patients.

Newly described:

• This study indicates good effectiveness of intravitreal aflibercept 8 mg in real-world setting. A significant reduction of disease activity parameters in SD-OCT after loading phase with 3 monthly injections is shown, while BCVA remains stable. This finding applies to both pre-treated as well as therapy-naïve eyes.

Keywords

retina - age-related macular degeneration - AMD - Aflibercept - real-world

Schlüsselwörter

Netzhaut - Aflibercept 8 mg - AMD - Anti-VEGF

Publication History

Received: 06 March 2025

Accepted: 08 July 2025

Accepted Manuscript online:
15 July 2025

Article published online:
01 September 2025

• References

• 1 Congdon N, OʼColmain B, Klaver CC. Eye Diseases Prevalence Research Group. Causes and Prevalence of Visual Impairment Among Adults in the United States. Arch Ophthalmol 2004; 122: 477-485
• 2 Wong WL, Su X, Li X. et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2014; 2: e106
• 3 Ciombor KK, Berlin J. Aflibercept–a Decoy VEGF Receptor. Curr Oncol Rep 2014; 16: 368
• 4 Bhisitkul RB. Vascular endothelial growth factor biology: clinical implications for ocular treatments. Br J Ophthalmol 2006; 90: 1542-1547
• 5 Rakic J-M, Lambert V, Devy L. et al. Placental Growth Factor, a Member of the VEGF Family, Contributes to the Development of Choroidal Neovascularization. Invest Ophthalmol Vis Sci 2003; 44: 3186-3193
• 6 Heier JS, Brown DM, Chong V. et al. Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration. Ophthalmology 2012; 119: 2537-2548
• 7 Wykoff CC, Brown DM, Reed K. et al. Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial. JAMA Ophthalmol 2023; 141: 834-842
• 8 Lanzetta P, Schulze A, Schmidt-Ott U. et al. Intravitreal Aflibercept 8 mg Injection in Patients With Neovascular Age-Related Macular Degeneration: 60-Week and 96-Week Results from the Phase 3 PULSAR Trial. Presented at the 23rd European Society of Retina Specialists (EURETINA) Congress. Accessed April 11, 2025 at: https://investor.regeneron.com/static-files/06016223-ff10-4fff-b9bb-3162f0ef27d9
• 9 Hosoda S, Sakurada Y, Fukuda Y. et al. Short-Term Outcomes of Three Consecutive Monthly Loading Administrations of Aflibercept 8 Mg for Treatment-Naïve Exudative Age-Related Macular Degeneration. Pharmaceuticals (Basel) 2025; 18: 438
• 10 Matsumoto H, Hoshino J, Numaga S. et al. Retinal vasculitis after intravitreal aflibercept 8 mg for neovascular age-related macular degeneration. Jpn J Ophthalmol 2024; 68: 531-537
• 11 Sambhara D, Vakharia P, Eichenbaum DA. Real-world efficacy and safety of 8 mg aflibercept in neovascular AMD: a case series. BMJ Open Ophthalmol 2025; 10: e002091
• 12 Binder KE, Bleidißel N, Charbel Issa P. et al. Noninfectious Intraocular Inflammation After Intravitreal Aflibercept. JAMA Ophthalmol 2025; 143: 499-506
• 13 Hashiya N, Maruko I, Miyaguchi Y. et al. Intraocular inflammation after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration: a case report. BMC Ophthalmol 2025; 25: 42
• 14 Hoffmann L, Michels S, Eandi C. et al. Aflibercept high-dose (8 mg) related intraocular inflammation (IOI) – a case series. BMC Ophthalmol 2024; 24: 520
• 15 Sisk RA. Occlusive Retinal Vasculitis After Aflibercept 8 mg Injection for Wet Macular Degeneration. Retin Cases Brief Rep 2025;
• 16 Keenan TD, Vitale S, Agrón E. et al. Visual Acuity Outcomes after Anti–Vascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report Number 19. Ophthalmol Retina 2020; 4: 3-12
• 17 Anderson WJ, da Cruz NFS, Lima LH. et al. Mechanisms of sterile inflammation after intravitreal injection of antiangiogenic drugs: a narrative review. Int J Retina Vitreous 2021; 7: 37
• 18 Cox JT, Eliott D, Sobrin L. Inflammatory Complications of Intravitreal Anti-VEGF Injections. J Clin Med 2021; 10: 981
• 19 Galati G, Tafazoli S, Sabzevari O. et al. Idiosyncratic NSAID drug induced oxidative stress. Chem Biol Interact 2002; 142: 25-41
• 20 Kreipe HH. Medikamentös induzierte Knochenmarkveränderungen. Pathologie (Heidelb) 2022; 43: 256-262
• 21 Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007; 96: 1788-1795
• 22 Zehetner C, Kirchmair R, Huber S. et al. Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema. Br J Ophthalmol 2013; 97: 454-459
• 23 Carneiro ÂM, Costa R, Falcão MS. et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab. Acta Ophthalmol 2012; 90: e25-e30
• 24 Matsuyama K, Ogata N, Matsuoka M. et al. Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol 2010; 94: 1215-1218
• 25 Bressler NM, Boyer DS, Williams DF. et al. Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials. Retina 2012; 32: 1821-1828
• 26 Zarbin MA. Anti-VEGF Agents and the Risk of Arteriothrombotic Events. Asia Pac J Ophthalmol 2018; 7: 63-67
• 27 Sobolewska B, Fehrenbacher B, Münzer P. et al. Human Platelets Take up Anti-VEGF Agents. J Ophthalmol 2021; 2021: 8811672
• 28 Pascutti MF, Erkelens MN, Nolte MA. Impact of Viral Infections on Hematopoiesis: From Beneficial to Detrimental Effects on Bone Marrow Output. Front Immunol 2016; 7: 364
• 29 Zheng P, Chang X, Lu Q. et al. Cytopenia and autoimmune diseases: A vicious cycle fueled by mTOR dysregulation in hematopoietic stem cells. J Autoimmun 2013; 41: 182-187