Aflibercept and faricimab restore endothelial barrier function in retinal disease to a similar extent in a preclinical study

A new preclinical study¹ of the effects of aflibercept (Eylea, Regeneron Pharmaceuticals) and faricimab (Vabysmo-svoa, Genentech) showed that the two treatments were equal in their ability to maintain or restore the retinal endothelial barrier function and resultant visual integrity, according to Tobias Strunz, PhD, and colleagues. They attributed this result mainly to inhibiting vascular endothelial growth factor (VEGF-A₁₆₅) binding to its receptor. Strunz is from Research & Early Development, Bayer AG, Wuppertal, Germany.

The current intravitreal treatments for neovascular age-related macular degeneration (nAMD), macular edema secondary to retinal vein occlusion, and diabetic macular edema (DME) inhibit VEGF-A binding to its receptors (VEGFRs) on the cell surface to decrease vascular permeability.^2,3 However, the drugs’ designs, binding affinities for VEGF-A, and abilities to neutralize targets other than VEGF-A differ.³

Regarding the two drugs under study, Strunz and colleagues noted, “Aflibercept acts as a decoy receptor comprising the second extracellular domain (ECD) of human VEGFR-1 and third ECD of human VEGFR-2 attached to the human immunoglobulin Fc fragment.⁴ Faricimab is a bispecific monoclonal antibody that can simultaneously bind VEGF-A and angiopoietin-2 (ANG2)²; however, in clinical studies, the co-inhibition of ANG2 and VEGF-A receptor binding did not show superiority to the inhibition of VEGF-A receptor binding alone in visual acuity and/or anatomic outcomes.⁵”

The investigators undertook this in vitro comparison study because of the high patient heterogeneity in anti-VEGF treatment responses, such as the need for shorter or extended treatment intervals,³ and visual acuity and anatomic gains, they explained.

“A better understanding of the molecular mechanisms associated with the clinical response is needed, especially in the context of drugs for which superiority in outcomes has not been demonstrated in direct comparison,⁵” they commented.

Comparison study methodology

In this in vitro study, Strunz and colleagues used a human umbilical vein endothelial cell (HUVEC)-based model to evaluate the aflibercept and faricimab. The cells in were exposed to VEGF-A₁₆₅, and then treated with aflibercept (1.7 nM) or faricimab (2.0 nM) either simultaneously as a preventive therapy or 24 hours later as a therapeutic/rescue therapy, they explained.

The investigators measured the cell-layer permeability, global transcriptomic changes by RNA sequencing, and VEGF-A₁₆₅–induced release of angiogenesis-related proteins.

What did the analysis reveal?

The investigators reported that treating the cells with aflibercept or faricimab “prevented a VEGF-A₁₆₅–triggered increase of HUVEC cell-layer permeability (P = 0.0005). In the therapeutic/rescue setting, either drug temporally improved the cell-layer integrity (P = 0.0001).”

Their results also showed the following:

• In both settings, preventive and therapeutic/rescue, aflibercept was non-inferior to faricimab (P < 0.0001 for both comparisons).

• Aflibercept and faricimab comparably down-regulated VEGF-A₁₆₅–induced angiogenesis-related genes.

• Aflibercept and faricimab equipotently suppressed or reversed VEGF-A₁₆₅ up-regulation of ANGPT2 gene expression and ANG2 protein in culture supernatant.

• VEGF-A₁₆₅–driven TEK gene expression and soluble Tie2 increase in culture supernatant was reversed with aflibercept and faricimab in both settings.

The primary study result was that the two anti-VEGF drugs that were evaluated were equally effective in their abilities to restore the endothelial barrier function. However, they noted, additional blockade of ANG2 with faricimab did not improve endothelial barrier integrity beyond VEGF-A₁₆₅ blockade alone with aflibercept, despite the significantly up-regulated ANG2 expression after VEGF-A₁₆₅ stimulation.

Strunz and colleagues commented, “This research also provides insights into the molecular mechanisms of anti-VEGF agents blocking VEGF-A only and those simultaneously blocking VEGF-A and ANG-2. Taken together, a higher dose of an anti-VEGF-A agent, rather than ANG2 co-blockade, likely supports anatomic improvements (ie, endothelial barrier function recovery by limiting retinal fluid retention) observed in some patients treated with FAR.”^6,7

They emphasized that neutralization of VEGF-A in the eye over the long term is crucial for maintaining the benefits of anti-VEGF-A therapy. “High binding affinity and maintenance of effective ocular drug concentrations play a key role for durable pharmacologic activity and clinical outcomes. A recent clinical study evaluating aflibercept 8 mg showed maintenance of the anti-VEGF-A response up to 156 weeks.⁸”

References
1. Strunz T, Rao M, Prinz F, et al. Aflibercept and faricimab equipotently restore endothelial barrier function. Invest Ophthalmol Vis Sci. 2026;67:5. doi: https://doi.org/10.1167/iovs.67.8.5
2. Liberski S, Wichrowska M, Kocięcki J. Aflibercept versus faricimab in the treatment of neovascular age-related macular degeneration and diabetic macular edema: a review. Int J Mol Sci. 2022;23:9424.
3. ElSheikh RH, Chauhan MZ, Sallam AB. Current and novel therapeutic approaches for treatment of neovascular age-related macular degeneration. Biomolecules. 2022;12:1629.
4. Eylea HD. Center for Drug Evaluation and Research Application. Application number BLA761355. [cited 2024 October 8, 2025]; Available from:https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/761355Orig1s000SumR.pdf.
5. Kalavar M, Sridhar J. Clinical trials and real-world studies examining faricimab and high-dose aflibercept for wet age-related macular degeneration and diabetic macular edema. Curr Opin Ophthalmol. 2025;36:189–98.

6. Bleidissel N, Weichenberger M, Maier M, Spielberg N, Feucht N. Improved functional and morphological outcomes with faricimab in nAMD eyes with poor response to prior intravitreal anti-VEGF therapy. Int Ophthalmol. 2025;45:177.
7. Neo EZO, Liang KWO, Toh ZH, et al. Real world outcomes of faricimab in treatment resistant neovascular age-related macular degeneration among Asian patients. Sci Rep. 2025;15:33672.
8. Ghorayeb G. Aflibercept 8 mg in diabetic macular edema: 156-week results from the PHOTON extension study. Invest Ophthalmol Vis Sci. 2025;66:2339. Meeting abstract.