The dry retina paradox: interpreting MERLIN in clinical practice

Persistent retinal fluid is a key topic in the management of neovascular age-related macular degeneration (AMD). Despite regular anti-vascular endothelial growth factor (anti-VEGF) therapy, a substantial proportion of patients continue to show intraretinal or subretinal fluid (SRF) on optical coherence tomography (OCT) (1), often prompting clinicians to intensify treatment (2) or switch agents (3,4). The MERLIN study was designed to address precisely this clinical scenario, evaluating noninferiority of fixed monthly dosing of brolucizumab 6 mg in comparison to aflibercept 2 mg in eyes with neovascular AMD and persistent fluid (5). The MERLIN study followed patients for 2 years. Results showed that brolucizumab 6 mg achieved noninferior best-corrected visual acuity (BCVA) outcomes, but superior anatomic outcomes compared with aflibercept 2 mg. These findings extend the previously reported 52-week results (6) and confirm that brolucizumab 6 mg exerts a strong and sustained effect on central retinal thickness (CRT) and resolution of intraretinal fluid (IRF) and SRF.

Results across all follow-ups showed that a substantially higher proportion of eyes with neovascular AMD treated with brolucizumab 6 mg achieved resolution of IRF and SRF, and a reduction in CRT, and that these results were greater than those observed with aflibercept 2 mg. From a purely anatomical standpoint, and when retinal fluid is used as a key marker of disease activity and treatment response, the MERLIN study illustrates that brolucizumab is a highly potent anti-VEGF agent. However, anatomical response poorly correlates with BCVA and visual function (7). This is also the case in the MERLIN study, which illustrates the limitations of an anatomy-first interpretation of treatment success. Despite superior anatomic outcomes, the mean BCVA remained essentially unchanged from baseline in both treatment arms at 104 weeks. Thus, visual outcomes were comparable between groups, and no functional advantage emerged in favor of brolucizumab. This dissociation between anatomy and vision is clinically important and echoes observations from other studies and consensus papers on neovascular AMD (8,9). This dissociation between anatomical and functional outcomes may become even more relevant as artificial intelligence-based OCT analysis and decision-support systems increasingly enter clinical practice. Algorithms trained primarily on anatomical biomarkers may risk reinforcing an anatomy-first treatment paradigm, underscoring the need to interpret imaging findings in the context of visual function and patient-centered outcomes.

Several factors likely explain this finding. Participants in the MERLIN study had longstanding disease, prior exposure to anti-VEGF therapy, and high baseline BCVA [73.4±7.4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the brolucizumab 6 mg group, 73.8±7.2 ETDRS letters in the aflibercept 2 mg group], creating a ceiling effect that limits further BCVA improvement (5). For clinicians, this underscores that an aggressive approach towards anatomic drying does not necessarily translate into additional functional benefit once visual potential is largely exhausted.

The clinical relevance of the MERLIN study is ultimately defined by its safety findings. The incidence of intraocular inflammation, including retinal vasculitis and retinal vascular occlusion, was higher with brolucizumab 6 mg than with aflibercept 2 mg throughout the study period. These events, while relatively infrequent, are clinically significant. Some inflammatory events were associated with persisting clinically significant vision loss. These safety signals are not unexpected and are consistent with prior reports for brolucizumab (10,11). What the MERLIN study adds is clarity regarding the risk profile under continuous monthly dosing in a previously treated population (12-14). The results strongly support current recommendations that brolucizumab 6 mg should be administered on a case-by-case basis and in an infrequent treatment regimen. Fixed treatment regimens with short treatment intervals should be used cautiously, especially in the era of modern durable anti-VEGF therapy, where long treatment intervals provide good visual outcomes with lower treatment burden (15,16).

For everyday practice, the implications are more pragmatic rather than paradigm-shifting. The MERLIN study does not suggest that brolucizumab should be abandoned in eyes with persistent fluid, but it does reinforce that treatment decisions must be guided by a careful balance between visual outcomes, anatomic ambition, and safety, while also being guided by the patients’ desires and wishes. In patients with residual fluid but stable vision, further intensification of therapy may offer limited functional gain while exposing patients to increased risk. Conversely, in selected cases where fluid is felt to be vision-threatening and alternative options are limited, or in cases where durable treatment options are warranted and other anti-VEGF drugs provide insufficient results, brolucizumab used within recommended dosing intervals may remain a reasonable consideration (17).

In conclusion, the 2-year results of the MERLIN study confirm the strong anatomic efficacy of brolucizumab, demonstrate BCVA noninferiority, and define the safety limits of such an approach. For clinical practice, the message is nuanced but clear: superior anatomic outcomes alone are insufficient to justify increased treatment intensity if they do not translate into meaningful visual benefit and come at the cost of increased risk. The MERLIN study thus reinforces a patient-centered, risk-balanced approach to managing persistent retinal fluid in neovascular AMD.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0002/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0002/coif). L.J.C. reports honorarium for lectures from AbbVie and Bayer, and serves on advisory boards for AbbVie, Novartis, and Roche. Y.S. reports honorarium for lectures from Bayer, Roche, and Santen, and is the inventor of a patent on biomarkers for polypoidal choroidal vasculopathy (WO2020007612A1). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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