What are the biggest ongoing questions involving Eylea (aflibercept) for the treatment of Age-related Macular Degeneration (AMD) in geriatric patients?

Ongoing Questions Regarding Eylea (Aflibercept) for Age-Related Macular Degeneration

The most pressing unresolved questions involve optimal long-term dosing strategies, durability of treatment response beyond 2 years, and identifying which patients can safely extend treatment intervals or discontinue therapy altogether.

Key Unresolved Clinical Questions

1. Optimal Treatment Regimen and Dosing Intervals

There remains no consensus on the ideal treatment protocol for aflibercept in AMD. 1 The American Academy of Ophthalmology acknowledges three competing approaches—monthly/bimonthly injections, treat-and-extend, or PRN (as-needed)—without establishing superiority of any single method. 1

• Monthly vs. extended dosing: While aflibercept every 8 weeks after three loading doses showed comparable first-year efficacy to monthly ranibizumab or aflibercept, the guidelines note that "there is no consensus about the ideal treatment intervals with anti-VEGF agents." 1

• Treat-and-extend protocols: This approach adjusts intervals based on treatment response, but optimal extension criteria and maximum safe intervals remain undefined. 1 Real-world data suggests intervals can extend to 11.2±3.5 weeks at 4 years, but standardized protocols are lacking. 2

• PRN regimens: Guidelines caution that PRN bevacizumab may be "slightly less effective than other monthly anti-VEGF regimens," but whether this applies equally to aflibercept remains unclear. 1

2. Long-Term Efficacy and Durability Beyond 2 Years

Vision gains achieved in the first 2 years are not consistently maintained with longer follow-up, representing a critical knowledge gap. 1

• The CATT study demonstrated that "vision gains during the first 2 years were not maintained at the 5-year follow-up visit, but 50% of patients maintained a VA of 20/40." 1

• Real-world data shows initial gains can be maintained at 4 years with reasonable treatment burden, but this represents observational evidence rather than controlled trial data. 2

• The question remains: What factors predict long-term responders versus those who lose initial gains, and how should treatment be modified for non-responders?

3. Exit Strategy and Treatment Discontinuation Criteria

Guidelines lack clear, evidence-based criteria for when patients can safely stop treatment or move to observation-only protocols. 1

• One real-world study found 35% of patients reached undefined "exit criteria" and continued with three-monthly observation only, but these criteria are not standardized. 2

• The American Academy of Ophthalmology recommends that "patients at exceptionally high risk may be examined more frequently (every 6-12 months) in an effort to detect asymptomatic CNV," but provides no specific thresholds for discontinuation. 1

4. Comparative Effectiveness: Aflibercept vs. Other Anti-VEGF Agents

While aflibercept was noninferior to ranibizumab in pivotal trials, real-world comparative effectiveness data remains limited. 1

• The USPSTF found that "aflibercept was noninferior to ranibizumab in likelihood of less than 15 ETDRS letters of visual acuity loss or more than 15 letters of visual acuity gain" across three trials. 1

• However, questions persist about whether aflibercept's theoretical advantages (higher VEGF-A affinity, binding of VEGF-B and PlGF) translate to clinically meaningful differences in specific patient subgroups. 3, 4

• Preliminary data suggests patients non-responsive to other anti-VEGF agents and those with special pathologies (polypoidal choroidopathy, retinal angiomatous proliferation) may benefit from switching to aflibercept, but robust evidence is lacking. 3

5. Higher-Dose Aflibercept (8 mg) in Pretreated Patients

The recently approved aflibercept 8 mg formulation shows promise for extended dosing intervals, but real-world data is scarce. 5

• Early evidence demonstrates "prolonged intervals between injections (5.5 weeks vs. 7 weeks), reduced disease activity, stable CST, and stable BCVA" in switched patients, but this represents limited observational data from 22 eyes. 5

• Critical unknowns include: optimal patient selection for 8 mg dosing, comparative effectiveness versus standard 2 mg dosing, and long-term safety profile in diverse populations.

6. Predictors of Treatment Response and Personalization

No validated biomarkers exist to predict which patients will respond optimally to aflibercept or require intensified treatment. 1, 3

• Guidelines note that "there is a subgroup of patients that present with persistent fluid after the loading dose that could benefit from monthly injections or personalized proactive treatment," but identification criteria remain undefined. 3

• The role of OCT and OCTA in guiding individualized treatment decisions requires further validation. 1

7. Safety Concerns and Long-Term Adverse Events

While short-term safety is well-established, questions remain about long-term systemic and ocular risks. 1

• Endophthalmitis rates are low (cumulative ≤1.0% over 1 year in VIEW studies), but long-term infection risk with extended treatment duration is incompletely characterized. 1

• "All anti-VEGF treatments may carry theoretical risks for systemic arterial thromboembolic events and increased intraocular pressure, although the results of clinical trials studying these risks remain inconclusive." 1

• The FDA label notes that aflibercept "adversely affected female and male reproductive systems in cynomolgus monkeys," but human fertility effects remain unstudied. 6

8. Cost-Effectiveness and Treatment Burden

Despite theoretical cost advantages with less frequent dosing, real-world cost-effectiveness data comparing aflibercept to other anti-VEGF agents is limited. 4

• Initial projections suggested aflibercept at $1,850 per dose would be cost-effective with bimonthly dosing, but actual treatment patterns often require more frequent administration. 4

• The balance between reducing injection frequency (patient burden) and maintaining optimal visual outcomes remains incompletely defined.

Common Pitfalls to Avoid

• Do not assume bimonthly dosing is appropriate for all patients after loading doses; many require more frequent treatment to maintain disease control. 1, 3

• Avoid rigid adherence to any single protocol without monitoring individual response; anatomic and functional outcomes should guide treatment intervals. 1

• Do not discontinue AREDS2 supplementation in fellow eyes at high risk; this can reduce advanced AMD risk by 36% over 10 years. 1

• Ensure patients understand the need for prompt reporting of new symptoms (metamorphopsia, vision loss) even during extended treatment intervals. 1