What are the new anti-Vascular Endothelial Growth Factor (VEGF) agents?

New Anti-VEGF Agents

The newest anti-VEGF agents include faricimab (a bispecific antibody targeting both VEGF-A and angiopoietin-2), high-dose aflibercept 8mg, and brolucizumab, which offer extended dosing intervals and represent the most recent advances beyond the established agents ranibizumab, aflibercept, and bevacizumab.

Currently Available Anti-VEGF Agents

Established Agents

• Ranibizumab (Lucentis) is a recombinant humanized antibody fragment that binds and inhibits VEGF-A, FDA-approved for neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vein occlusion 1, 2
• Aflibercept (Eylea) is a VEGF inhibitor approved for neovascular AMD, macular edema following RVO, diabetic macular edema, diabetic retinopathy, and retinopathy of prematurity 3
• Bevacizumab is commonly used off-label for central-involved diabetic macular edema and other retinal vascular diseases 1

Newer Generation Agents

Brolucizumab (Beovu) is a human VEGF inhibitor FDA-approved for neovascular AMD and diabetic macular edema 4. This represents a more recent addition to the anti-VEGF armamentarium with potential for extended dosing.

Faricimab (Vabysmo) is the first bispecific monoclonal antibody that neutralizes both VEGF-A and angiopoietin-2 (Ang-2), offering dual pathway inhibition 5, 6, 7. The American Academy of Ophthalmology recognizes faricimab as one of the anti-VEGF agents for treating center-involved diabetic macular edema 6. This dual mechanism targeting both the VEGF and Ang/Tie-2 pathways addresses the complex pathophysiology of retinal vascular diseases more comprehensively than single-target agents 7.

High-dose aflibercept (8mg) represents an advancement in dosing strategy, demonstrating noninferiority in landmark trials (PHOTON and PULSAR) with extended dosing intervals compared to standard aflibercept 8.

Key Advantages of Newer Agents

Extended Treatment Intervals

• Faricimab allows extending intervals between injections up to 12-16 weeks (3-4 months) in nAMD and DME patients, significantly reducing treatment burden 7
• The American Academy of Ophthalmology recommends anti-VEGF administration every 4-8 weeks during the first 12 months, with fewer injections in subsequent years 5
• High-dose aflibercept similarly demonstrates extended dosing capability while maintaining efficacy 8

Dual Pathway Targeting

• Faricimab's bispecific mechanism addresses both VEGF-driven angiogenesis and Ang-2-mediated vascular instability, potentially offering superior durability 7, 9
• Pivotal trials (YOSEMITE and RHINE) established faricimab as noninferior to standard anti-VEGF therapy with superior durability 8
• Multi-targeted therapies may be more efficacious than VEGF-A-only agents, as targeting VEGF alone may be insufficient for optimal outcomes 9

Clinical Considerations

Treatment Selection

• For center-involved diabetic macular edema with moderate visual impairment (20/50 or worse), aflibercept provides superior vision outcomes compared to bevacizumab 1
• Faricimab is appropriate for patients requiring reduced injection frequency while maintaining disease control 5, 6
• The American Diabetes Association supports anti-VEGF therapy as first-line treatment for center-involved diabetic macular edema, with faricimab included among the recommended agents 6

Monitoring Requirements

• Regular OCT monitoring is essential to evaluate treatment response and determine continuation criteria 5
• Typical treatment patterns involve 6-8 injections in the first year, with fewer injections in subsequent years 5
• Extended dosing intervals with newer agents must be balanced against the need for more frequent monitoring to ensure disease control 8

Safety Profile

• Ocular adverse event rates are similar between faricimab and traditional anti-VEGF monotherapy 10
• Standard precautions for endophthalmitis, retinal detachment, and increased intraocular pressure apply to all intravitreal anti-VEGF agents 3

Important Caveats

Real-world evidence for high-dose aflibercept remains limited compared to the extensive clinical trial data, warranting cautious interpretation of its long-term effectiveness 8. While faricimab has demonstrated durability in both trials and real-world studies, improvements in visual acuity remain variable across different patient populations 8.

Non-response and resistance can still occur with newer agents despite multi-pathway targeting, as the pathophysiology of retinal vascular diseases is complex and incompletely addressed by current therapies 7, 9. For persistent macular edema despite anti-VEGF treatment, alternative approaches including laser photocoagulation or intravitreal corticosteroids should be considered 1.