The History of Anti-VEGF Therapy

Anti-VEGF therapy transformed retinal medicine by targeting vascular endothelial growth factor (VEGF), a protein that can cause abnormal blood-vessel growth and leakage in the eye. If you have conditions such as wet age-related macular degeneration or diabetic macular oedema, anti-VEGF injections may help protect your central vision.

Before these treatments became available, you had fewer effective options for managing serious retinal conditions. As researchers learned more about VEGF, they developed treatments that target an important pathway involved in abnormal blood-vessel growth and leakage, giving you a more effective way to manage several sight-threatening retinal conditions.

What Is VEGF?

VEGF, or vascular endothelial growth factor, is a protein that helps control blood-vessel growth and leakage. In several retinal diseases, increased VEGF activity can contribute to abnormal blood-vessel growth, increased vascular permeability and fluid leakage.

This leakage can affect the cells responsible for clear central vision and may lead to swelling or sight loss. Understanding how VEGF affects your retina helped researchers develop anti-VEGF treatments that can target this process.

Research Insight

The scientific story behind anti-VEGF treatment began decades before the first eye injection was approved. In 1983, Senger and colleagues described a tumour-secreted vascular permeability factor that increased vascular leakage. Subsequent work established that this factor was closely related to what became known as VEGF.

During the 1990s, research increasingly linked VEGF with abnormal blood-vessel growth and leakage inside the eye. A landmark 1994 study provided evidence connecting VEGF with ocular neovascularisation, helping establish the biological rationale for eventually blocking VEGF as a retinal treatment.

Why Did VEGF Become an Important Target?

Researchers found that VEGF plays an important role in abnormal blood-vessel growth and leakage inside your eye. When too much VEGF is present, it can contribute to retinal swelling and damage that affects your vision.

By blocking VEGF, doctors gained a way to target a key biological pathway involved in abnormal blood-vessel growth and leakage rather than relying only on treatments directed at established abnormal vessels or their consequences. This discovery helped create more effective treatment options for people with certain sight-threatening retinal conditions.

Key Milestones in the History of Anti-VEGF Therapy

Year	Milestone	Why it mattered
1983	Vascular permeability factor described	Helped establish the biology of vascular leakage
1989	VEGF characterised as an endothelial growth factor	Provided a specific molecular target for later therapies
1994	VEGF linked strongly with ocular neovascular disease	Helped establish its importance in retinal pathology
2004	Pegaptanib trial results and FDA approval	First FDA-approved anti-VEGF treatment for neovascular AMD
2005	Early ocular bevacizumab reports	Demonstrated the potential of broader VEGF blockade in AMD
2006	Ranibizumab; MARINA and ANCHOR	Showed that anti-VEGF could not only reduce vision loss but improve mean visual acuity
2011	CATT and aflibercept approval	Established comparative bevacizumab/ranibizumab evidence and expanded treatment choice
2015	DRCR.net Protocol T	Clarified comparative anti-VEGF outcomes in diabetic macular oedema
2019	Brolucizumab approved in the US	Added a longer-interval anti-VEGF option but later highlighted important safety considerations
2022	Faricimab approved	Introduced dual VEGF-A/angiopoietin-2 targeting
2023	High-dose aflibercept 8 mg approved in the US	Developed to support longer intervals between injections
2024	First interchangeable aflibercept biosimilars approved by the FDA	Expanded US biologic treatment choice

Treatment Before Anti-VEGF Therapy

Before anti-VEGF injections became available, you had fewer treatment options for wet age-related macular degeneration (AMD). Laser photocoagulation and verteporfin photodynamic therapy were important options for selected forms of neovascular AMD, but their ability to preserve or improve visual acuity was more limited than the outcomes later demonstrated in pivotal ranibizumab trials.

These earlier treatments were important steps in retinal care, but they had limitations. The development of anti-VEGF therapy gave you a more targeted approach to controlling abnormal blood-vessel growth and leakage.

The Arrival of Pegaptanib

Pegaptanib was one of the first anti-VEGF treatments developed for wet age-related macular degeneration (AMD). If you had wet AMD at the time, this treatment offered a new way to slow vision loss by targeting VEGF activity in your eye.

Clinical research published in 2004 showed that selective VEGF inhibition could reduce vision loss in people with wet AMD. This helped establish the potential of anti-VEGF therapy and paved the way for newer treatments that you can receive today.

The First FDA-Approved Anti-VEGF Eye Treatment

The US FDA approved pegaptanib, marketed as Macugen, for neovascular age-related macular degeneration (AMD) on 17 December 2004. If you had wet AMD, this became an important new treatment option for slowing vision loss.

Pegaptanib was given as an intravitreal injection approximately every six weeks. This approach marked an important step towards the injection-based anti-VEGF treatments that you may receive today.

Bevacizumab Enters Ophthalmology

Bevacizumab was originally developed to treat cancer rather than eye conditions. If you had neovascular age-related macular degeneration (AMD), early reports in 2005 showed that bevacizumab could reduce retinal swelling and potentially improve your vision.

This was an important development for you because it showed that anti-VEGF treatment could target abnormal blood-vessel activity in your retina. As research progressed, you had more opportunities to benefit from anti-VEGF therapy, with bevacizumab helping to shape the treatment approaches used in retinal care today.

Why Was Bevacizumab Important?

Bevacizumab became widely used off-label in retinal medicine because it offered an accessible anti-VEGF option. If you had neovascular AMD, this treatment could help reduce abnormal blood-vessel activity and protect your vision.

In the one-year CATT trial, bevacizumab and ranibizumab produced equivalent mean visual-acuity outcomes when the two medicines were administered according to the same schedule. Some anatomical and safety findings differed and required separate interpretation. This gave you another option for managing wet AMD while also helping shape modern anti-VEGF care.

The Development of Ranibizumab

Ranibizumab was specifically developed to target VEGF inside the eye. If you had wet age-related macular degeneration (AMD), its development gave you a treatment designed specifically to control the abnormal blood-vessel growth and leakage affecting your retina.

The FDA approved ranibizumab for wet AMD on 30 June 2006, marking an important milestone in retinal care. For you, this helped establish anti-VEGF injections as a major treatment approach for protecting vision and managing neovascular AMD.

The MARINA Trial

The landmark MARINA trial showed that ranibizumab could reduce the risk of vision loss in people with neovascular age-related macular degeneration (AMD). If you had wet AMD, this was an important development because treatment could offer you more than simply slowing further vision loss.

The trial also found that some people could achieve improvements in visual acuity. This changed what you could realistically expect from treatment and helped establish anti-VEGF therapy as a major approach to protecting and improving vision.

The ANCHOR Trial

The ANCHOR trial compared ranibizumab with photodynamic therapy in people with predominantly classic neovascular age-related macular degeneration (AMD). If you had this form of wet AMD, the results showed that ranibizumab could offer you better visual outcomes than photodynamic therapy.

This was an important step in changing how you could be treated for wet AMD. The findings helped establish anti-VEGF injections as a leading approach for protecting your vision and managing abnormal blood-vessel growth.

The CATT Trial

The CATT trial directly compared ranibizumab with off-label bevacizumab for neovascular age-related macular degeneration (AMD). If you had wet AMD, the study showed that both medicines could provide similar effects on your visual acuity when used with comparable treatment approaches.

These findings were important because they gave you another effective anti-VEGF option for managing wet AMD. The results also helped doctors make more informed decisions about which treatment may be appropriate for you.

The Arrival of Aflibercept

Aflibercept was approved in the US for wet age-related macular degeneration (AMD) in 2011, giving you another anti-VEGF treatment option. It works by blocking VEGF and other related growth factors involved in abnormal blood-vessel growth and leakage.

After an initial period of more frequent treatment, aflibercept could be given at longer intervals for some patients. This meant you could potentially have fewer injections while still receiving effective control of your condition.

Expanding Beyond Wet AMD

Anti-VEGF treatment later expanded beyond wet age-related macular degeneration (AMD) to other retinal conditions. If you have diabetic macular oedema, diabetic retinopathy or retinal vein occlusion, anti-VEGF injections may help reduce abnormal leakage and protect your vision.

The wider use of aflibercept and ranibizumab gave you more treatment options for managing these sight-threatening conditions. This expansion also showed how targeting VEGF could help control retinal damage caused by different diseases.

Diabetic Macular Oedema

Anti-VEGF therapy transformed the treatment of diabetic macular oedema by reducing fluid leakage and helping improve vision. If you have this condition, these injections can help reduce swelling in your retina and protect your sight.

A major comparative trial found that aflibercept, bevacizumab and ranibizumab could all improve visual outcomes. However, the level of benefit varied depending on your starting visual acuity, showing why treatment needs to be tailored to you.

Moving Away from Fixed Monthly Injections

Anti-VEGF treatment has gradually become more individualised, so you may not need injections at the same fixed interval indefinitely. Your specialist can adjust the timing according to your vision, OCT findings and signs of retinal disease activity.

• Initial Treatment: You may need more frequent injections at the beginning to bring abnormal leakage or swelling under control.
• Treat-and-Extend: Your specialist may gradually increase the interval between injections when your retina remains stable.
• OCT Monitoring: Retinal scans can help determine whether fluid, swelling or other signs of disease activity have returned.
• Shorter Intervals When Needed: Your treatment interval may be reduced again if your condition becomes more active or your retinal findings worsen.

The aim is to reduce unnecessary treatment burden while continuing to protect your vision and control the retinal disease. Your injection schedule should therefore be based on how your individual condition responds rather than on one fixed timetable for every patient.

The Development of Faricimab

Faricimab introduced a newer approach by targeting both VEGF-A and angiopoietin-2. If you have wet age-related macular degeneration or diabetic macular oedema, this dual-target treatment may help control the abnormal blood-vessel activity and leakage affecting your retina.

The FDA approved faricimab in January 2022 for these conditions, adding another option to your treatment choices. Its development also marked an important step towards treatments designed to provide effective disease control with potentially longer intervals between injections.

Longer-Lasting Anti-VEGF Treatment

High-dose aflibercept 8 mg was developed to support longer treatment intervals while maintaining disease control. At its 2023 US approval, treatment for wet age-related macular degeneration could be given every 8 to 16 weeks after the initial monthly doses. Current UK product information allows treatment intervals to be individualised and, in selected patients with stable visual and anatomical outcomes, extended further.

This can make your treatment schedule more convenient and reduce the number of clinic visits you need. However, your injection interval will depend on how your retina responds and whether your disease remains controlled.

Biosimilars and Wider Treatment Choice

Biosimilars are versions of established biological medicines that are designed to provide comparable treatment effects. If you need anti-VEGF therapy, their growing availability may give you more treatment options and potentially improve access to care.

In 2024, the FDA approved the first interchangeable aflibercept biosimilars, marking another step in the development of retinal treatment. As more options become available, your specialist can consider factors such as effectiveness, safety, availability and treatment suitability when choosing your therapy.

UK Guidance Note

Many landmark anti-VEGF developments occurred first through US FDA approvals, which is why dates such as the 2004 pegaptanib, 2006 ranibizumab and 2011 aflibercept approvals are important historical milestones. However, treatment availability and recommendations for UK patients also depend on UK licensing, NICE guidance and current product information.

For example, NICE recommended faricimab for eligible wet AMD in 2022, bevacizumab gamma is now specifically licensed in the UK for neovascular AMD, and current UK aflibercept 8 mg product information allows individualised treatment intervals that may be extended up to 6 months in selected patients with stable visual and anatomical outcomes.

Myth vs Fact

Myth	Fact
Anti-VEGF treatment cures the underlying cause of every retinal disease.	VEGF inhibition targets an important disease pathway, but AMD, diabetes and retinal vein occlusion are multifactorial conditions.
Pegaptanib produced the same visual improvements later seen with ranibizumab.	Pegaptanib was historically important for reducing visual loss, while MARINA and ANCHOR later demonstrated substantial visual-acuity gains with ranibizumab.
Bevacizumab was originally developed as an eye medicine.	The original bevacizumab formulation was developed for cancer and later used off-label in ophthalmology.
Ranibizumab was the first ocular anti-VEGF medicine.	Pegaptanib was FDA-approved for neovascular AMD in 2004, before ranibizumab in 2006.
All anti-VEGF medicines target exactly the same molecules.	Their mechanisms differ; for example, faricimab targets VEGF-A and angiopoietin-2, while aflibercept binds VEGF-A, VEGF-B and PlGF.
Every patient still needs a monthly injection indefinitely.	Modern treatment can use individualised treat-and-extend or longer-interval regimens depending on the drug and disease activity.
Biosimilars are ordinary generic medicines.	Biosimilars are biological medicines shown to be highly similar to an approved reference biological product.
A longer injection interval is automatically better.	Disease control and vision remain the priority, and some patients require shorter intervals.

Key Takeaways

• VEGF research developed from early vascular-permeability work in the 1980s to evidence linking VEGF with ocular neovascularisation in the 1990s.
• Pegaptanib became the first FDA-approved anti-VEGF treatment for neovascular AMD in 2004.
• MARINA and ANCHOR changed expectations by showing that ranibizumab could preserve and, on average, improve visual acuity.
• Bevacizumab became widely used off-label in retinal medicine, and CATT later showed visual-acuity equivalence with ranibizumab when the drugs were given according to the same schedule.
• Aflibercept expanded treatment options from 2011, including regimens requiring fewer injections than fixed monthly ranibizumab in pivotal trials.
• Protocol T showed that relative anti-VEGF outcomes in DMO can depend on baseline visual acuity.
• Brolucizumab’s history highlighted important risks of intraocular inflammation, retinal vasculitis and vascular occlusion.
• Faricimab added dual VEGF-A/angiopoietin-2 inhibition, while aflibercept 8 mg further expanded longer-interval treatment strategies.
• Biosimilars and UK-authorised bevacizumab gamma have further expanded retinal treatment choice.
• Modern anti-VEGF care remains individualised: treatment choice and interval depend on the retinal diagnosis, visual response, imaging findings, safety and current UK licensing/guidance.

Frequently Asked Questions

1. When was anti-VEGF therapy first introduced for eye disease?
   Pegaptanib became the first FDA-approved anti-VEGF treatment for neovascular age-related macular degeneration (AMD) in December 2004. Its approval marked an important change in how wet AMD could be treated.
2. Why was VEGF targeted for retinal diseases?
   VEGF can promote abnormal blood-vessel growth and leakage in the retina. Blocking VEGF can therefore help reduce fluid accumulation and abnormal vessel activity that may threaten your vision.
3. What was the first anti-VEGF drug approved for wet AMD?
   Pegaptanib, marketed as Macugen, was the first anti-VEGF drug approved by the FDA specifically for neovascular AMD. It helped establish intravitreal anti-VEGF injections as an important treatment approach.
4. When was ranibizumab approved for wet AMD?
   The FDA approved ranibizumab for wet AMD in June 2006. Clinical trials such as MARINA and ANCHOR helped demonstrate its ability to reduce vision loss and, in some patients, improve visual acuity.
5. Why is bevacizumab used in retinal medicine?
   Bevacizumab was originally developed as a cancer treatment but was later used off-label in ophthalmology because it blocks VEGF. Research, including the CATT trial, helped establish its effectiveness as an anti-VEGF option for neovascular AMD.
6. When did aflibercept become available for retinal disease?
   Aflibercept was approved in the US for wet AMD in 2011. It provided another way to inhibit VEGF and allowed longer treatment intervals for some patients compared with earlier fixed treatment schedules.
7. Which retinal conditions can anti-VEGF injections treat?
   Anti-VEGF therapy is used for several retinal conditions, including wet AMD, diabetic macular oedema and retinal vein occlusion. Depending on your condition, treatment may help reduce retinal swelling, abnormal blood-vessel growth and fluid leakage.
8. What was the significance of the CATT trial?
   The CATT trial compared ranibizumab with bevacizumab for neovascular AMD. It found that both could provide similar visual outcomes when used according to comparable treatment strategies, helping clinicians make more informed treatment decisions.
9. How has anti-VEGF treatment become less frequent over time?
   Treatment has increasingly moved away from automatically giving injections at fixed monthly intervals. Treat-and-extend approaches allow your specialist to adjust the interval according to your OCT scans, vision and signs of retinal disease activity.
10. What is the future of anti-VEGF therapy?
    Recent developments have focused on longer-lasting treatments, new mechanisms and greater treatment choice. High-dose aflibercept 8 mg, faricimab and biosimilar medicines are examples of developments that may help make retinal treatment more flexible and accessible.

Final Thoughts: How Anti-VEGF Therapy Has Changed Retinal Care

The history of anti-VEGF therapy shows how understanding the role of VEGF transformed the management of serious retinal diseases. From the early use of pegaptanib to newer treatments such as faricimab and high-dose aflibercept, developments in retinal medicine have given you more effective and flexible ways to manage conditions that can threaten your sight.

If you have concerns about your eyesight, you can contact our team at Eye Clinic London to discuss your symptoms and arrange a comprehensive assessment if appropriate.

References:

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2. Gragoudas, E.S., Adamis, A.P., Cunningham, E.T. Jr, Feinsod, M. and Guyer, D.R., for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group (2004) ‘Pegaptanib for neovascular age-related macular degeneration’, New England Journal of Medicine, 351(27), pp. 2805–2816. Available at: https://pubmed.ncbi.nlm.nih.gov/15625332/
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4. Hang, A., Feldman, S., Amin, A.P., Ochoa, J.A.R. and Park, S.S. (2023) ‘Intravitreal anti-vascular endothelial growth factor therapies for retinal disorders’, Pharmaceuticals, 16(8), article 1140. Available at: https://www.mdpi.com/1424-8247/16/8/1140
5. Bressler, N.M., Kaiser, P.K., Do, D.V., Nguyen, Q.D., Park, K.H., Woo, S.J., Sagong, M., Bradvica, M., Kim, M.Y., Kim, S. and Sadda, S.R. (2024) ‘Biosimilars of anti-vascular endothelial growth factor for ophthalmic diseases: a review’, Survey of Ophthalmology, 69(4), pp. 521–538. Available at: https://www.sciencedirect.com/science/article/pii/S0039625724000298