Early observations and pilot data that first suggested a new direction
Before anti-VEGF therapy, wet AMD treatment relied on thermal laser photocoagulation and photodynamic therapy (PDT) with verteporfin, which could slow but not reverse vision loss. The TAP and VIP trials established PDT as the standard of care in the early 2000s, but outcomes remained poor with most patients still losing vision. The discovery that vascular endothelial growth factor (VEGF) drove choroidal neovascularization opened a revolutionary therapeutic target. Pegaptanib (Macugen), an RNA aptamer targeting VEGF-165, became the first anti-VEGF agent approved for wet AMD in 2004 based on the VISION trial, demonstrating that VEGF inhibition could reduce vision loss compared to sham injection.
Landmark RCTs and pivotal trials that established the evidence base
The MARINA and ANCHOR trials fundamentally transformed wet AMD treatment by demonstrating that monthly ranibizumab (Lucentis) injections not only prevented vision loss but actually improved visual acuity in a significant proportion of patients. MARINA showed that 95% of ranibizumab-treated patients avoided moderate vision loss versus 62% with sham, and one-third gained 15 or more letters. ANCHOR demonstrated ranibizumab superiority over PDT with verteporfin. These results established intravitreal anti-VEGF injection as the new standard of care and represented one of the most dramatic treatment advances in ophthalmology history.
Follow-up studies, subgroup analyses, and real-world validation
The CATT trial demonstrated that bevacizumab (Avastin), available at a fraction of the cost, was non-inferior to ranibizumab for visual acuity outcomes, fundamentally changing access to anti-VEGF therapy worldwide. The VIEW 1 and VIEW 2 trials established aflibercept (Eylea) as an alternative with the advantage of less frequent dosing (every 8 weeks after loading). More recently, faricimab (Vabysmo), a bispecific antibody targeting both VEGF-A and angiopoietin-2, demonstrated in the TENAYA and LUCERNE trials that up to 16-week dosing intervals were achievable. The treat-and-extend paradigm has largely replaced fixed monthly dosing, reducing treatment burden while maintaining outcomes.
Integration into clinical practice guidelines and recommendations
Major ophthalmic societies worldwide now recommend anti-VEGF therapy as first-line treatment for wet AMD. The American Academy of Ophthalmology Preferred Practice Pattern guidelines endorse intravitreal anti-VEGF agents as the standard of care, with treat-and-extend protocols increasingly preferred over fixed monthly dosing. The Royal College of Ophthalmologists and NICE guidelines support both ranibizumab and aflibercept, with bevacizumab widely used off-label in resource-limited settings. Guidelines emphasize prompt treatment initiation and regular OCT-guided monitoring to optimize outcomes.
American Academy of Ophthalmology Preferred Practice Pattern
Anti-VEGF therapy is recommended as first-line treatment for neovascular AMD. Treat-and-extend regimens are acceptable alternatives to fixed monthly dosing.
NICE Technology Appraisal TA778
Faricimab is recommended as an option for treating wet AMD in adults when anti-VEGF therapy is indicated.
Now
Current standard of care and ongoing research directions
The wet AMD treatment landscape continues to evolve toward longer-duration therapies and reduced injection burden. High-dose aflibercept (Eylea HD) and the port delivery system with ranibizumab (Susvimo) represent approaches to extend treatment intervals to 3-6 months. Biosimilar anti-VEGF agents are entering the market, promising to reduce costs. Gene therapy approaches (such as RGX-314) aim to provide continuous VEGF suppression from a single treatment. The field is moving toward personalized treatment algorithms guided by AI-enhanced OCT biomarkers, with the ultimate goal of maintaining vision with the fewest possible interventions.
Why is bevacizumab still widely used despite not having an FDA indication for wet AMD?+
The CATT trial demonstrated bevacizumab is non-inferior to ranibizumab for visual acuity outcomes at approximately 1/40th the cost. Many healthcare systems worldwide use bevacizumab off-label as first-line therapy, particularly in resource-limited settings, supported by equivalent efficacy data from multiple randomized trials.
What is treat-and-extend, and why has it replaced monthly injections?+
Treat-and-extend involves injecting at every visit while progressively extending the interval between visits if the macula is dry on OCT. This approach reduces the number of injections and clinic visits compared to fixed monthly dosing while maintaining similar visual outcomes, as demonstrated in multiple randomized trials including TREX-AMD.
How has faricimab changed the treatment paradigm?+
Faricimab is the first bispecific antibody approved for wet AMD, targeting both VEGF-A and angiopoietin-2. In the TENAYA and LUCERNE trials, over 75% of patients achieved dosing intervals of 12 weeks or longer, with some reaching 16-week intervals, substantially reducing treatment burden compared to earlier anti-VEGF agents.
