Introduction
Neovascular age-related macular degeneration (nAMD) remains a primary cause of severe vision loss globally. While the advent of vascular endothelial growth factor (VEGF) inhibitors revolutionized the management of this condition, the treatment burden associated with frequent intravitreal injections remains a significant challenge for both patients and healthcare systems. In clinical practice, the goal is to achieve a dry macula while extending treatment intervals to the maximum extent possible without compromising visual acuity. Faricimab, the first bispecific antibody designed for intraocular use, targets both VEGF-A and angiopoietin-2 (Ang-2), aiming to provide enhanced vascular stability and durability compared to traditional anti-VEGF monotherapy.
Recent data from the phase 3 TENAYA and LUCERNE randomized clinical trials (RCTs) demonstrated that faricimab is noninferior to aflibercept while allowing for extended dosing intervals in a majority of patients. A critical question for clinicians is whether early anatomical responses can serve as a prognostic indicator for long-term durability. This post hoc analysis investigates whether rapid resolution of intraretinal fluid (IRF) and subretinal fluid (SRF) by week 12 is associated with the ability to maintain extended dosing intervals through week 112.
Highlights
- Early anatomical response (fluid resolution at week 12) is strongly associated with long-term faricimab durability in nAMD patients.
- Patients achieving a dry retina by week 12 were nearly twice as likely to maintain an every-16-week (Q16W) dosing schedule at the first extension opportunity.
- The predictive value of early fluid resolution persists through two years of treatment, supporting the use of early response as a clinical guide for personalized treat-and-extend regimens.
The Clinical Rationale for Dual Inhibition
The pathogenesis of nAMD involves not only VEGF-driven angiogenesis but also vascular instability characterized by vessel leakage and inflammation. While VEGF-A inhibition addresses the former, Ang-2 is a key driver of vascular destabilization and sensitization to VEGF. By inhibiting both pathways, faricimab aims to promote more robust vascular tie-2 signaling, leading to more durable anatomical and functional outcomes. The post hoc analysis of TENAYA and LUCERNE provides a deeper look into how this dual mechanism translates into clinical milestones, specifically the speed of retinal drying.
Study Design and Methodology
This post hoc analysis utilized data from the faricimab arms of the TENAYA and LUCERNE trials. These were randomized, double-masked, multicenter studies comparing faricimab (6 mg) up to every 16 weeks with aflibercept (2 mg) every 8 weeks. The study population consisted of treatment-naive participants with nAMD.
Intervention and Follow-up
Participants in the faricimab arm received four initial loading doses every 4 weeks. Disease activity was assessed at week 20 or 24, which served as the first opportunity to extend the treatment interval. From week 60 onwards, a treat-and-extend-based dosing regimen was implemented. The analysis focused on 552 participants whose dosing intervals were recorded at the initial assessment (week 20/24) and 478 participants who completed the study through week 112.
Definitions of Fluid Resolution
Rapid fluid resolution was defined as the complete absence of both intraretinal fluid (IRF) and subretinal fluid (SRF) at week 12, following the first three loading doses. Multinomial logistic regression was employed to calculate the odds ratios (OR) for achieving Q12W or Q16W dosing compared to the standard Q8W dosing, based on the fluid status at week 12.
Key Findings: Early Drying and Future Durability
The analysis revealed a compelling correlation between early anatomical success and long-term interval extension. Of the 552 participants evaluated at week 20 or 24, 265 (48%) achieved IRF and SRF resolution by week 12, while 287 did not.
Short-Term Durability (Weeks 20 and 24)
Patients who achieved a dry retina by week 12 were significantly more likely to be extended to a Q16W interval at the first assessment compared to those who still had fluid (OR, 1.99; 95% CI, 1.23-3.21; P = .005). Furthermore, these patients were also more likely to achieve at least a Q12W interval (OR, 1.77; 95% CI, 1.09-2.87; P = .02) than those without rapid resolution.
Long-Term Durability (Week 112)
The predictive power of early fluid resolution remained evident at the end of the two-year study period. Participants with a dry retina at week 12 were more likely to be on a Q16W dosing schedule at week 112 compared to those who had persistent fluid early in treatment (OR, 1.76; 95% CI, 1.10-2.83; P = .02). This suggests that the initial response to faricimab is not just a transient effect but an indicator of the underlying vascular stability achieved in the patient.
Expert Commentary and Clinical Implications
The findings from this post hoc analysis are highly relevant for the clinical management of nAMD. In an era where personalized medicine is becoming the standard, having early biomarkers to predict treatment intervals can help clinicians manage patient expectations and optimize clinic workflows. The ability of faricimab to achieve rapid drying in nearly half of the study population by week 12 is a testament to the efficacy of the dual VEGF/Ang-2 inhibition strategy.
Mechanistic Insights
The more rapid drying observed with faricimab compared to historical data with anti-VEGF monotherapy may be attributed to the stabilization of the retinal vasculature. Persistent fluid is often a sign of chronic vascular leakage that requires frequent suppression. By addressing the Ang-2 pathway, faricimab may reduce the ‘leakiness’ of the choroidal neovascularization (CNV) membranes more effectively, allowing for a more rapid return to a physiological state and, consequently, longer intervals between treatments.
Limitations
As a post hoc analysis, these results should be interpreted with caution. The study was not originally powered to detect these specific associations as primary endpoints. Additionally, while fluid resolution is a strong predictor, other factors such as baseline lesion type, patient age, and genetic predispositions also play roles in determining treatment durability.
Conclusion
The post hoc analysis of TENAYA and LUCERNE underscores the importance of early anatomical response in nAMD. Rapid resolution of IRF and SRF by week 12 with faricimab is a significant predictor of achieving and maintaining extended dosing intervals up to Q16W through two years. For clinicians, these data suggest that patients who respond quickly to the initial loading phase of faricimab are excellent candidates for aggressive interval extension, potentially reducing the overall treatment burden while maintaining visual outcomes.
Trial Registration and Funding
The TENAYA and LUCERNE trials were funded by F. Hoffmann-La Roche Ltd. ClinicalTrials.gov Identifiers: NCT03823287 and NCT03823300.
References
- Pitcher JD 3rd, Koh AHC, Tan CS, et al. Rapid Fluid Resolution and Durability With Faricimab in Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. Published online February 19, 2026. doi:10.1001/jamaophthalmol.2025.6365.
- Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of faricimab in neovascular age-related macular degeneration (TENAYA and LUCERNE): week 48 results of two priorised, double-masked, phase 3, non-inferiority trials. Lancet. 2022;399(10326):729-740.
- Khanani AM, Guymer RH, Basu K, et al. Faricimab in Neovascular Age-Related Macular Degeneration: 2-Year Outcomes From the TENAYA and LUCERNE Trials. Ophthalmology. 2024;131(1):54-66.
