Case series: Brolucizumab efficacy and safety in treating neovascular age-related macular degeneration

Abstract

Dear Editor,

Neovascular age-related macular degeneration (nAMD) is a leading cause of irreversible visual loss in older individuals and can significantly impact their quality of life and independence. Age-induced degeneration of the retinal pigment epithelium (RPE) leads to a hypoxia and chronic inflammation, which promote abnormal choroidal neovascularization (CNV) via vascular endothelial growth factor (VEGF) secretion.¹ This neovascularization disrupts retinal structure, causing exudation and vision impairment.

The advent of anti-VEGF agents, designed to reduce abnormal neovascularization by inhibiting VEGF, has been validated in various clinical studies. Brolucizumab (Beovu®) is a newer agent, comprising a 26 kDa humanized monoclonal single-chain variable fragment against VEGF-A, and has demonstrated comparable efficacy to existing agents in improving visual and anatomical outcomes with fewer required dosages, thereby lowering treatment burden.² In the MERLIN study, 6 mg injections of Beovu® at 4-week intervals led to more pronounced effect in reducing subretinal fluid (SRF) compared to aflibercept.² However, the safety profile of brolucizumab remains a concern due to the higher incidence of reported adverse effects in patients, including noninfectious intraocular inflammation (IOI), endophthalmitis, retinal vasculitis (RV), retinal vascular occlusion (RVO), and secondary glaucoma.³

Here, we report the clinical outcomes of five nAMD patients treated with Beovu® at the Macau Brightcare Medical Center between April 2017 and February 2023. Each patient received intravitreal Beovu® or a combination of Beovu® and other anti-VEGF agents (Table S1). The outcomes of these five patients treated for nAMD and polypoidal choroidal vasculopathy (PCV) illustrate variable responses to anti-VEGF therapies, as well as the potential for adverse effects with newer treatments.

Patient 1 presented with pigment epithelial detachment (PED) (Figure S1A) and significant improvement in the right eye following a Beovu® injection (Figure S1B), achieving improved best corrected visual acuity (BCVA) from 1.0 to 1.2 at 9 days, with stability at 43 days. OCT showed progressive resolution of PED without recurrence, suggesting a favorable response to Beovu® for initial PED resolution in nAMD.

Patient 2 initially showed improvement in BCVA and reduced SRF after three Lucentis® injections (Figure S2A,B). Three years later, recurrence with significant PED and SRF required further treatment. Beovu® injections stabilized the condition (Figure S2C,D), but BCVA only improved marginally to counting fingers. While Beovu® helped reduce fluid accumulation, the visual recovery remained limited, highlighting potential limitations in achieving functional gains in recurrent cases.

Patient 3 also presented with leakage (Figure S3A) and SRF (Figure S3B) in both fluorescein angiography and SD-OCT. He benefited from Beovu®, with BCVA improving from 0.8 to 1.0 and OCT demonstrating reduced intraretinal and subretinal fluid (Figure S3C). However, unlike Patient 2, no recurrence was observed during follow-up, suggesting a sustained effect in the early treatment of PCV-related PED.

Patient 4 had a long-standing history of treatment-resistant nAMD with limited visual acuity gains despite multiple Lucentis® and an Eylea® injections over 2 years. Following a recurrence marked by significant SRF and intraretinal fluid (IRF) (Figure S4A), Beovu® was administered over 7 months. This led to stable resolution of SRF and IRF, with no recurrence after 1 year and 3 months (Figure S4B). While Beovu® proved effective for structural improvement, functional recovery was not achieved, suggesting it may offer structural stabilization in chronic cases resistant to other anti-VEGFs.

Patient 5 presented recurrence of PCV 6 months after his latest Eylea® injection (Figure 1A). Upon initial improvement in BCVA after a single Beovu® injection (Figure 1B), he presented with inflammation and elevated intraocular pressure (IOP) days later (Figure 1C), leading to a diagnosis of IOI and RV. Intensive corticosteroid and IOP-lowering therapy were initiated, gradually resolving inflammation and improving retinal structure (Figure 1D), although vision deteriorated later. Additional Eylea® injections were required to manage new PED and subfoveal hemorrhage. This case underscores the risks associated with Beovu®, particularly IOI, IOP spikes, and RV, necessitating careful patient selection and monitoring.

Across these cases, responses to anti-VEGF therapies varied by treatment history, disease chronicity, and underlying pathology. Three patients treated with Beovu® after prior Lucentis® or Eylea® injections achieved fluid reduction, but one experienced an IOI event, consistent with literature linking brolucizumab to an increased IOI risk postaflibercept transition. This suggests that careful patient selection and monitoring are essential when switching therapies to mitigate inflammatory complications.

For dosing considerations, the HAWK and HARRIER trials recommend an initial loading phase of monthly Beovu® injections followed by maintenance every 8–12 weeks.⁴ Our findings suggest the potential for even longer intervals without loss of efficacy, as seen in Patient 4, who maintained stable vision over a year posttreatment. Notably, multiple studies reported a higher incidence of ocular adverse side effects in patients treated with Beovu compared to aflibercept. This incidence was higher at the 6 mg dose (3.1%–9.3%)^{2, 4} compared to 3 mg dose (1.4%),⁴ suggesting that an increased dosage raises the risk of adverse events, calling for careful consideration of more personalized dosing regimens. Given brolucizumab's potent effect but heightened risk profile at higher doses, a personalized dosing strategy balancing efficacy with safety is essential.

When IOI or RVO complications arise, prompt intervention with corticosteroids is critical to prevent irreversible visual impairment. Our case with brolucizumab-induced IOI demonstrates the rapid onset of symptoms and the need for regular early follow-up. In this instance, a prompt switch to a steroid regimen led to improvement, though visual acuity did not fully recover, underscoring the necessity for vigilance in monitoring post-Beovu® injection.

While traditional imaging like colored fundus photography and optical coherence tomography, may miss early inflammation indicators, laser flare-cell photometry (LFCP), which measures aqueous humor protein levels, has been proposed as a method for identifying IOI early.⁵ Research indicates that a threshold of 15 photon counts/millisecond in LFCP could signal brolucizumab-induced IOI, though further validation is needed. Implementing such noninvasive biomarkers into routine care could improve early diagnosis and intervention for at-risk patients.

In summary, Beovu® has proven to be an effective treatment for managing persistent retinal fluid and reducing central subfield thickness in conditions like nAMD, PED, and PCV, particularly in cases where other anti-VEGF therapies have failed. Its long-acting effect and its ability to extend dosing intervals, as seen in our case, reduce treatment burden for patients. However, the risk of intraocular inflammation, especially with higher doses and increased injection frequency, remains a significant concern. Personalized dosing regimens, early follow-up, and potentially biomarker-guided monitoring can help optimize outcomes while minimizing adverse events. Further research into predictive biomarkers and risk factors for intraocular inflammation may help improve safety and efficacy in long-term use.

Linling Cheng: Conceptualization (equal); data curation (equal); formal analysis (equal); writing—original draft (equal). Charlotte L. Zhang: Conceptualization (equal); data curation (equal); formal analysis (equal); writing—original draft (equal). Cheryl C. Lai: Data curation (equal); formal analysis (equal); writing—review and editing (equal). Ning Sun: Data curation (equal); writing—review and editing (equal). Hiuwa Hang: Conceptualization (equal); supervision (equal); writing—review and editing (equal). All authors approved the final version of the manuscript to be submitted for publication.

The authors declare no conflict of interest.

This study was approved by Ethics Committee of Macau Brightcare Hospital and written informed consents were obtained from all participant patients. All data were anonymized before analysis, and no new data were collected from participants.