What are the research gaps in faricimab (Anti-VEGF therapy) administration and usage, particularly in patients with diabetic macular edema or neovascular age-related macular degeneration?

Research Gaps in Faricimab Administration and Usage

Despite faricimab's FDA approval and inclusion in current treatment guidelines for diabetic macular edema and neovascular age-related macular degeneration, critical research gaps remain regarding optimal dosing intervals, long-term durability beyond 2 years, comparative effectiveness against newer agents, treatment-naïve versus switch populations, and predictive biomarkers for treatment response.

Key Evidence Gaps Identified

Long-Term Efficacy and Durability Data

• Current guidelines acknowledge faricimab as one of five anti-VEGF agents for center-involved diabetic macular edema, but long-term outcome data beyond the pivotal trials remains limited 1
• The YOSEMITE/RHINE and TENAYA/LUCERNE trials demonstrated efficacy through 96 weeks, with 62-78% of patients achieving 12-16 week dosing intervals, but data beyond 2 years is lacking 2
• Real-world evidence shows promising anatomical improvements and safety profiles, but follow-up periods in most studies range only 4-24 weeks, insufficient to assess sustained durability 3, 4
• Extension trials (AVONELLE-X and RHONE-X) are ongoing but not yet published, leaving a critical gap in understanding long-term outcomes and whether initial treatment gains are maintained over 3-5 years 2

Optimal Treatment Protocols and Personalized Dosing

• Guidelines recommend anti-VEGF therapy every 4-8 weeks during the first 12 months for diabetic macular edema, but specific protocols for faricimab's personalized treatment interval (PTI) approach in routine practice remain undefined 1
• The pivotal trials used fixed loading phases followed by PTI adjustments, but real-world implementation strategies and criteria for interval extension lack standardization 2, 5
• No head-to-head comparisons exist between faricimab and brolucizumab, the other extended-interval agent, leaving uncertainty about relative efficacy and durability 1
• Treat-and-extend protocols have been validated for ranibizumab and aflibercept, but whether faricimab's dual mechanism allows for different extension criteria remains unexplored 1

Treatment-Naïve Versus Switch Populations

• Most real-world evidence involves patients switched from other anti-VEGF agents due to inadequate response, with limited data on treatment-naïve patients starting with faricimab 6, 4
• Switch studies show anatomical improvements but variable visual acuity outcomes, with baseline characteristics (prior treatment duration, baseline CRT, baseline VA) correlating with post-switch results 6
• Whether faricimab should be first-line therapy versus reserved for inadequate responders to other anti-VEGF agents remains unresolved, as guidelines list it alongside other agents without preference hierarchy 1, 7
• The impact of prior anti-VEGF treatment history on faricimab response requires further investigation, particularly regarding treatment burden and cumulative injection numbers 6

Predictive Biomarkers and Patient Selection

• No validated biomarkers exist to predict which patients will achieve extended 16-week dosing intervals versus requiring more frequent injections 2, 5
• The STAIRWAY trial showed 65% of patients had no disease activity 12 weeks after loading, but criteria for identifying these patients prospectively are lacking 5
• Specific anatomical features (fluid types, pigment epithelial detachment characteristics) that predict faricimab response versus other anti-VEGF agents remain undefined 6, 4
• Guidelines note that aflibercept provides superior outcomes to bevacizumab in eyes with vision 20/50 or worse, but faricimab's comparative effectiveness in this subgroup is unknown 1

Safety and Adverse Event Profiles

• Long-term safety data beyond 2 years is absent, particularly regarding cumulative effects of dual VEGF-A and angiopoietin-2 inhibition 2, 4
• While short-term safety appears comparable to aflibercept in pivotal trials, real-world studies report no adverse events but have limited follow-up and small sample sizes 3, 4
• Specific risks in special populations (pregnancy, lactating women, patients with cardiovascular disease) remain unstudied, as guidelines note anti-VEGF risks in pregnancy are unknown 1
• The theoretical risk of systemic arterial thromboembolic events with anti-VEGF therapy remains inconclusive across all agents, including faricimab 1

Economic and Patient-Reported Outcomes

• Cost-effectiveness analyses comparing faricimab's extended dosing intervals against monthly or treat-and-extend regimens with other agents are lacking 4
• Guidelines acknowledge that anti-VEGF therapy requires greater visit frequency than panretinal laser, creating treatment burden, but faricimab's impact on this burden versus other agents is unquantified 1
• Patient-reported outcomes regarding quality of life, treatment satisfaction, and adherence with extended intervals are minimally reported in current literature 4
• The impact of nonintentional treatment lapses on outcomes with faricimab's extended intervals requires investigation, as guidelines note this risk with anti-VEGF therapy generally 1

Comparative Effectiveness Research

• No direct comparative trials exist between faricimab and the newer high-dose aflibercept (8mg) formulation, both designed for extended dosing 1
• Protocol T demonstrated differences between bevacizumab, ranibizumab, and aflibercept in eyes with vision 20/50 or worse, but faricimab was not included 1
• Whether faricimab's dual mechanism provides advantages in specific clinical scenarios (persistent fluid, recalcitrant cases, specific fluid patterns) versus single-target agents remains unexplored 2, 3

Implementation in Clinical Practice

• Optimal strategies for transitioning patients from fixed monthly dosing to PTI intervals lack evidence-based protocols 2
• The role of adjunctive focal laser with faricimab for persistent diabetic macular edema is undefined, whereas guidelines support this combination with other anti-VEGF agents 1
• Criteria for switching from faricimab to alternative therapies (corticosteroids, other anti-VEGF agents) when response is inadequate are not established 1