An Introduction to Anti-VEGF Therapy

Jia Xuan Tan

Introduction

Anti-vascular endothelial growth factor (anti-VEGF) therapy has transformed the management of several retinal conditions that once led to significant and irreversible vision loss. Prior to its introduction, diseases such as neovascular age-related macular degeneration (nAMD) frequently resulted in rapid, irreversible central vision decline. The advent of intravitreal anti-VEGF injections now allows most patients to maintain vision, and many experience meaningful improvement. This article aims to provide a foundational understanding of the therapeutic mechanism, primary clinical indications, current treatment paradigms, and the future trajectory of anti-VEGF agents, highlighting developments focused on maximizing efficacy and reducing patient burden.

Mechanism of Action

VEGF is a pivotal signalling protein that drives both normal physiological angiogenesis and pathological neovascularisation central to many ocular diseases. In retinal diseases, excessive VEGF-A expression drives two primary sight-threatening events (1):

  1. Pathological Neovascularisation: VEGF stimulates the proliferation and migration of vascular endothelial cells, leading to the formation of abnormal, fragile new blood vessels prone to bleeding.
  2. Vascular hyperpermeability: VEGF disrupts endothelial tight junctions, weakening the blood-retinal barrier (BRB), leading to fluid leakage and macular oedema (1).

Anti-VEGF agents are designed to inhibit these processes by binding to VEGF-A, thereby preventing its ligand from binding to its cognate receptors, primarily VEGFR-1 and VEGFR-2 on the surface of endothelial cells (2). This blockade achieves the following therapeutic effects:

  1. Reduced vascular leakage: Inhibition of VEGF-mediated signalling rapidly reverse permeability of the microvasculature, restoring the integrity of the BRB and leading to the resolution of macular oedema.
  2. Neovascular regression: Chronic inhibition of VEGF-A deprives the abnormal new blood vessels (such as choroidal neovascular membranes) of their essential growth signal, leading to their involution (3).

The intravitreal injection route ensures high therapeutic concentrations is delivered directly to the target tissue (the retina and choroid) while minimising systemic exposure and associated adverse events (3).

Clinical Indications

Anti-VEGF therapy is now standard of care for several retinal diseases where pathological neovascularisation or vascular leakage is the primary driver of vision loss.

Neovascular Age-Related Macular Degeneration (nAMD)

Structural breaks in Bruch’s membrane allow choroidal vessels to grow into the subretinal space. These newly formed vessels are fragile and prone to leakage or bleeding, resulting in macular fluid and rapid visual deterioration. Anti-VEGF therapy effectively suppress choroidal neovascular membrane (CNV) activity (4).

Diabetic Macular Oedema (DMO)

Chronic hyperglycaemia results in pericyte loss, microaneurysm formation, capillary leakage, and breakdown of the BRB. Increased inflammation and VEGF expression lead to accumulation of fluid within the macula. Anti-VEGF injections reduce this macular oedema and vascular leakage thereby improving visual function (4).

Retinal Vein Occlusion (RVO)

Venous obstruction creates increased venous congestion, haemorrhage and capillary non-perfusion. The resultant ischaemic state stimulates VEGF expression and hence resulting in  leaky vessels and retinal oedema. Anti-VEGF therapy effectively reduces macular oedema and improves visual function in both branch and central RVO (5).

Commonly used Anti-VEGF Agents

Ranibizumab (Lucentis®) is a recombinant humanised antibody fragment that was the first intravitreal anti-VEGF to gain FDA approval for nAMD in 2006. Its biosimilars are increasingly favoured due to lower cost and comparable efficacy (6).

Aflibercept (Eylea®) is a recombinant fusion protein that was approved by the FDA in 2011 for treatment of nAMD.  It binds multiple ligands with high affinity, allowing for generally longer treatment intervals (6).

Faricimab (Vabysmo®), approved in 2022, is a dual-pathway inhibitor targeting VEGF-A and angiopoietin-2, offering extended durability (6).

Common Treatment Regimens

Treat-and-Extend Strategy: After an initial loading phase of at least 3 monthly injections, the injection interval is gradually lengthened (typically by 2 to 4-week increments) up to a maximum of 12 to 16 weekly, if the disease remains stable on OCT, or shortened if recurrence is detected. Treatment is given at every scheduled visit regardless of disease status. This proactive approach minimizes recurrence episodes and provides an optimal balance between disease control and clinic efficiency (7, 8).

Fixed dosing:Injections are administered at predetermined, regular intervals (e.g., every 8 or 12 weeks), independent of clinical activity. While predictable, this approach can lead to overtreatment in stable eyes or undertreatment in eyes with persistent activity, posing a high clinic burden (7).

Pro Re Nata (PRN)/As needed: This involves a monthly monitoring visit with treatment given only when signs of active disease (fluid, bleeding) recur in an effort to reduce need for injection. This strategy carries a higher risk of undertreatment and potential vision loss (7).

Challenges and Future Directions

The chronic nature of retinal diseases necessitates long-term monitoring and repeated injections, imposing a significant logistical and financial strain on healthcare systems globally (9). Ongoing research is heavily focused on reducing the treatment burden without compromising visual outcomes.

  • Longer-acting drugs: The development of newer agents(e.g., high-dose Aflibercept) and molecules with engineered longer half-lives is aimed at reliably achieving longer injection intervals.
  • Sustained-release drug delivery: Technologies such as the Port Delivery System (PDS) offer the potential for continuous drug delivery, requiring refills only every 6 months or longer, significantly reducing injection frequency (9).
  • Growing use of biosimilars: The expiring patents (eg.  Ranibizumab 2022, Aflibercept 2025) have spurred the development and use of biosimilars. Their growing availability is critical for maintaining high-volume retinal service in a cost-effective manner while maintaining clinical efficacy (10).

Conclusion

Anti-VEGF therapy has revolutionised the management of retinal disease, offering vision stability and improvement for conditions that previously resulted in severe sight loss. For early-career doctors, understanding how these drugs work, when they are used, and how the treatment landscape is evolving is essential for effective ophthalmological practice. As innovations continue to prioritise durability and personalised care, the focus remains on providing effective, patient-centred treatment.

References

  1. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019 Mar 7;176(6):1248-64.
  2. Fogli S, Del Re M, Rofi E, Posarelli C, Figus M, Danesi R. Clinical pharmacology of intravitreal anti-VEGF drugs. Eye. 2018 Jun;32(6):1010-20.
  3. Zarbin, M.A., 2018. Anti-VEGF agents and the risk of arteriothrombotic events. The Asia-Pacific Journal of Ophthalmology, 7(1), pp.63-67.
  4. Hang A, Feldman S, Amin AP, Ochoa JA, Park SS. Intravitreal anti-vascular endothelial growth factor therapies for retinal disorders. Pharmaceuticals. 2023 Aug 11;16(8):1140.
  5. Campa C, Alivernini G, Bolletta E, Parodi MB, Perri P. Anti-VEGF therapy for retinal vein occlusions. Current drug targets. 2016 Mar 1;17(3):328-36.
  6. Cen S, Liu S, Zhao M, Tang L. Comparative efficacy and safety of faricimab, aflibercept, conbercept, and ranibizumab for neovascular age-related macular degeneration: a systematic review and network meta-analysis. European Journal of Pharmacology. 2025 Nov 25:178406.
  7. Lanzetta P, Loewenstein A, Vision Academy Steering Committee. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti–vascular endothelial growth factor therapy of macular diseases. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2017 Jul;255(7):1259-73.
  8. Chaikitmongkol V, Sagong M, Lai TY, Tan GS, Ngah NF, Ohji M, Mitchell P, Yang CH, Ruamviboonsuk P, Wong I, Sakamoto T. Treat-and-extend regimens for the management of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy: consensus and recommendations from the Asia-Pacific Vitreo-retina Society. The Asia-Pacific Journal of Ophthalmology. 2021 Nov 1;10(6):507-18
  9. Xu M, Fan R, Fan X, Shao Y, Li X. Progress and challenges of anti-VEGF agents and their sustained-release strategies for retinal angiogenesis. Drug design, development and therapy. 2023 Dec 31:3241-62.
  10. Kapur M, Nirula S, Naik MP. Future of anti-VEGF: biosimilars and biobetters. International journal of retina and vitreous. 2022 Jan 4;8(1):2.

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