
==== Front
Ophthalmol Ther
Ophthalmol Ther
Ophthalmology and Therapy
2193-8245
2193-6528
Springer Healthcare Cheshire

39214946
1022
10.1007/s40123-024-01022-w
Original Research
High-Dose Brolucizumab for Refractory Neovascular Age-Related Macular Degeneration Resistant to Standard-Dose Brolucizumab
Kim Jinsoo
Park Min Seon
Cho Bum-Joo
http://orcid.org/0000-0003-1543-981X
Kwon Soonil magicham@naver.com
magicham@hallym.or.kr

grid.256753.0 0000 0004 0470 5964 Department of Ophthalmology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 22, Gwanpyeong-ro 170 beon-gil, Dongan-gu, Anyang, Gyeonggi 14068 Republic of Korea
30 8 2024
30 8 2024
10 2024
13 10 27892797
10 7 2024
13 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Introduction

The aim of this study was to evaluate the efficacy and safety of escalating the dosage of intravitreal brolucizumab in patients with refractory neovascular age-related macular degeneration (AMD).

Methods

This retrospective study included 17 eyes of 17 patients with refractory AMD treated with high-dose brolucizumab (12 mg/0.1 ml) for over 12 months. Patients initially received at least one anti-vascular endothelial growth factor (anti-VEGF) agent and were switched to standard-dose brolucizumab (6 mg/0.05 ml). Those who showed a suboptimal response to standard-dose treatment had their dosage of brolucizumab escalated.

Results

Visual acuity was maintained from 68.3 ± 3.4 letters to 70.7 ± 3.2 letters after 12 months of high-dose treatment (P = 0.128). Central subfield thickness was 343.7 ± 17.0 μm before high-dose treatment and 316.7 ± 18.5 μm at 12 months (P = 0.083). The proportions of patients with subretinal fluid and serous pigment epithelial detachment significantly decreased from 82.4% to 41.2% and from 52.9% to 17.6%, respectively, after high-dose treatment (P = 0.039 and P = 0.031, respectively). The treatment interval extended from 7.2 ± 2.4 weeks to 10.2 ± 2.2 weeks after switching to standard-dose brolucizumab (P < 0.001) and was maintained at 13.5 ± 2.8 weeks after increasing the dose (P = 0.154). No severe ocular adverse events were observed.

Conclusions

High-dose brolucizumab was effective in patients who did not respond to standard-dose brolucizumab after switching from previous anti-VEGF agents. Increasing the dosage could offer sustained disease control and reduce the treatment burden for patients with refractory AMD.

Keywords

Beovu®
Intravitreal injection
Real world
Recalcitrant age-related macular degeneration
Super dose
issue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2024
==== Body
pmcKey Summary Points

Why carry out this study?	
Novel treatment approaches for neovascular age-related macular degeneration (AMD) are essential to reduce the frequency of injections and the associated socioeconomic burden while maintaining or improving treatment outcomes.	
The study hypothesized that increasing the dosage of intravitreal brolucizumab in patients with refractory AMD would reduce the need of frequent injections and enhance visual and anatomical outcomes.	
What was learned from the study?	
High-dose brolucizumab was effective not only in maintaining visual acuity and treatment intervals but also in decreasing the proportions of patients with subretinal fluid and serous pigment epithelial detachment.	
High-dose brolucizumab can be a viable treatment option for patients with refractory AMD, providing sustained disease control and reducing the treatment burden.	

Introduction

Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of neovascular age-related macular degeneration (AMD) [1]. Over the last decade, pivotal studies have shown that anti-VEGF injections can prevent vision loss in most patients [2]. Since AMD poses a substantial treatment burden globally and becomes an increasingly important public health concern due to aging populations and greater longevity [3], innovative treatments are essential to reduce the burden of treatment and monitoring visits while ensuring treatment effectiveness and safety [4, 5]. Options for injections include monthly, every 2 or 3 months (extended-fixed), as needed (pro re nata, PRN), or treat-and-extend [6]. Longer intervals between treatments could decrease the burden on patients, caregivers, and healthcare systems, potentially leading to improved outcomes [7].

Anti-VEGF treatment shows variable clinical outcomes, and retinal fluid remains in many eyes with AMD despite regular and individualized treatment [8–10]. Nonetheless, there are no established guidelines for treating AMD patients who do not respond to routine anti-VEGF treatment. For example, monthly injections may be effective, but this is not a perfect solution and may increase the treatment burden [8, 9]. The HARBOR [11, 12] and SAVE trials [13, 14] reported that increasing the dose of ranibizumab in AMD reduced the number of intravitreal injections or improved visual acuity. Regarding switching method, recent studies on the use of brolucizumab for recalcitrant AMD unresponsive to other agents have reported promising outcomes [15–17].

Brolucizumab (Beovu®, Novartis) is a recently used anti-VEGF comprising a humanized single-chain antibody fragment with a molecular weight of 26 kDa, allowing for higher molar dosing than previous anti-VEGF therapies [10]. A small molecular weight (26 kDa) combined with a high concentration gradient between the vitreous and retina may enhance drug distribution into the retina, while higher molar doses of the drug may be cleared more slowly from the eye, thus extending its duration of action [10]. Despite its higher drying effect, special attention is required from ophthalmologists when initiating brolucizumab treatment due to the higher incidence of intraocular inflammation during the loading phase [18].

We hypothesized that for patients who switched to brolucizumab and had a suboptimal response, increasing the dosage could decrease the frequency of required injections and enhance vision and anatomical outcomes. Therefore, this study was conducted to evaluate the efficacy and safety of high-dose intravitreal brolucizumab for refractory AMD with a suboptimal response to a standard dose of brolucizumab.

Methods

This retrospective study included patients with refractory AMD who received intravitreal high-dose brolucizumab injections as switch therapy for more than 12 months at Hallym University Sacred Heart Hospital. The study was approved by the Institutional Review Board of Hallym University Sacred Heart Hospital (IRB No. Hallym 2024-06-003), and informed consent was waived due to the retrospective nature of the chart review study. The study adhered to the tenets of the Declaration of Helsinki.

Patients initially began treatment with at least one anti-VEGF agent, such as aflibercept (Eylea®, Regeneron Pharmaceuticals, Inc.), ranibizumab (Lucentis®, Genentech, Inc.), or bevacizumab (Avastin®, Genentech, Inc.). If the response to these treatments was insufficient, the treatment was switched to standard-dose brolucizumab (6 mg/0.05 ml) without a loading dose, maintaining the previous treatment interval. Those who were unable to maintain a treatment interval of 8 weeks or more due to increased fluid or decreased visual acuity were given high-dose brolucizumab (12 mg/0.1 ml). Exclusion criteria included patients with type 3 macular neovascularization (MNV), advanced cataract, a history of vitrectomy, prior laser or photodynamic therapy, or any history of other retinal diseases or glaucoma.

Each patient underwent a comprehensive ophthalmic examination, including visual acuity assessment, color fundus photography, fluorescein angiography, indocyanine green angiography, and spectral-domain optical coherence tomography (Spectralis® HRA + OCT, Heidelberg Engineering, Heidelberg, Germany). Visual acuity was converted to the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score for analysis. Central subfield thickness was defined as the average thickness of the macula in the central 1 mm ETDRS grid and measured using the built-in software [19]. Angiographies were conducted before initiating treatment to determine the subtypes of AMD.

Patients with AMD were classified into three subtypes based on the type of MNV: type 1 or 2 MNV, polypoidal choroidal vasculopathy (PCV). Type 1 MNV involves neovascularization occurring beneath the retinal pigment epithelium, while type 2 MNV arises from the choroid and proliferates in the subretinal space between the retinal pigment epithelium and the neurosensory retina [20]. The diagnosis of PCV was based on the presence of branching choroidal vascular networks and polypoidal lesions upon indocyanine green angiography, in accordance with the EVEREST study group criteria [21].

Patients were treated with treat-and-extend regimen and as-needed regimen. In the treat-and-extend regimen, treatments were extended by 2 or 4 weeks if no signs of recurrent exudation were observed. Conversely, the intervals were shortened by 2 or 4 weeks if signs of increased exudation or new macular hemorrhage were detected. In the as-needed regimen, injections were administered if exudation or macular hemorrhage was observed. Injections were carried out using a standardized technique: anesthesia was applied with topical proparacaine 0.5%, the eye and surrounding areas were cleansed with povidone-iodine 5%, and a lid speculum was used. The injection site was marked with calipers, and injections were administered at volumes of 0.05 ml for the standard dose and 0.1 ml for the high dose. Providers wore gloves and were masked for the injection procedures. Post-injection, central retinal artery perfusion was verified, and any significant elevation in intraocular pressure was managed at the physicians’ clinical discretion.

To assess changes in continuous variables, we used the paired t test for normally distributed data and the Wilcoxon signed-rank test for data that did not follow a normal distribution. McNemar's test was used for the analysis of categorical variables to evaluate the differences in proportions before and after treatment. Statistical analyses were performed using Statistical Package for Social Sciences Version 20.0 (SPSS Inc., Chicago, IL, USA). P values < 0.05 were considered statistically significant.

Results

Among the 62 eyes of 62 patients who were switched to standard-dose brolucizumab due to an incomplete response to previous anti-VEGF treatment, 20 eyes (32.3%) again showed an incomplete response and were subsequently treated with high-dose brolucizumab. Of these, three eyes were excluded because the high-dose treatment period was less than 12 months. The demographic and clinical characteristics of the 17 eyes of 17 patients with AMD are summarized in Table 1. The mean age was 76.2 ± 8.4 years, and nine (52.9%) were male. Out of the 17 eyes, eight (47.1%) had type 1 MNV, 4 (23.5%) had type 2 MNV, and five (29.4%) had PCV. Five patients (29.4%) had been treated with one type of anti-VEGF agent, nine (52.9%) with two types, and three (17.6%) with three types. All eyes had previously received intravitreal anti-VEGF injections before switching to standard-dose brolucizumab, with a mean of 12.2 ± 6.6 intravitreal injections. Following the switch to standard-dose brolucizumab, they received a mean of 4.5 ± 2.3 injections. Due to insufficient response to standard-dose brolucizumab, high-dose brolucizumab was administered, averaging 5.9 ± 2.8 injections. The total treatment duration for the patients was 55.8 ± 35.0 months, with a follow-up period of 15.9 ± 5.2 months after switching to high-dose brolucizumab.Table 1 Demographic and clinical characteristics of patients

Characteristic	Total (n = 17)	
Age, year	76.2 ± 8.4	
Sex (male/female)	9/8	
Laterality (right/left)	9/8	
Lens status (phakia/pseudophakia)	7/10	
Systemic disease	
 Diabetes mellitus	6 (35.3)	
 Hypertension	14 (82.4)	
Type of age-related macular degeneration	
 Type 1	8 (47.1)	
 Type 2	4 (23.5)	
 Polypoidal choroidal vasculopathy	5 (29.4)	
Treatment regimen (as needed/treat and extend)	3/14	
No. of prior anti-VEGF agents	
 1 agent	5 (29.4)	
 2 agents	9 (52.9)	
 3 agents	3 (17.6)	
Follow-up period, month	
 After first anti-VEGF injection	55.8 ± 35.0	
 After a standard dose of brolucizumab	21.5 ± 6.7	
 After a high dose of brolucizumab	15.9 ± 5.2	
No. of intravitreal injections	
 Prior anti-VEGF agents	12.2 ± 6.6	
 Standard-dose brolucizumab	4.5 ± 2.3	
 High-dose brolucizumab	5.9 ± 2.8	
Values are presented as mean ± standard deviation or as n (%)

VEGF vascular endothelial growth factor

The mean visual acuity was 68.3 ± 3.4 letters before increasing the brolucizumab dosage and was maintained at 70.7 ± 3.2 letters after 12 months (P = 0.128) (Table 2). After 12 months, vision was maintained in 14 eyes (82.4%), with an improvement of more than 10 letters observed in two eyes (11.6%) and a decline of more than ten letters in one eye (5.9%). Moreover, the central subfield thickness remained stable, showing no significant change from 343.7 ± 17.0 μm to 316.7 ± 18.5 μm over 12 months (P = 0.083). Notably, the proportions of patients with subretinal fluid and serous pigment epithelial detachment significantly decreased (P = 0.039 and P = 0.031, respectively). However, the proportion of patients with intraretinal fluid showed no significant change (P = 0.219).Table 2 Visual and anatomical outcomes after increasing the dose of brolucizumab

	Before high dose	After 12 months	P	
ETDRS letters	68.3 ± 3.4	70.7 ± 3.2	0.128*	
Central subfield thickness (μm)	343.7 ± 17.0	316.7 ± 18.5	0.083†	
Intraretinal fluid, n (%)	8 (47.1)	4 (23.5)	0.219‡	
Subretinal fluid, n (%)	14 (82.4)	7 (41.2)	0.039‡	
Serous PED, n (%)	9 (52.9)	3 (17.6)	0.031‡	
Values are presented as mean ± standard deviation

ETDRS early treatment diabetic retinopathy study, PED pigment epithelial detachment

*Wilcoxon signed-rank test

†Paired t test

‡McNemar’s test

After switching from the previous agent to standard-dose brolucizumab, the treatment interval significantly extended from 7.2 ± 2.4 weeks to 10.2 ± 2.2 weeks (P < 0.001) (Table 3). Twelve months after escalating the brolucizumab dose, the treatment interval was 13.5 ± 2.8 weeks, showing no significant change compared to standard-dose brolucizumab (P = 0.154). Following the dosage increase, the treatment interval was extended by 2 weeks or more in six eyes (35.3%), maintained in eight eyes (47.1%), and needed reduction by 2 weeks or more in three eyes (17.6%). Before the dose increase, five eyes (29.4%) maintained a treatment interval of at least 12 weeks, compared to seven eyes (41.2%) after the dose escalation (P = 0.50).Table 3 Change in visual acuity and treatment interval

Characteristic	Total (n = 17)	
Vision change after standard-dose brolucizumab	
 Loss (≥ 10 letters lost)	1 (5.9)	
 Stable (< 10 letters gained/lost)	10 (58.8)	
 Gain (≥ 10 letters gained)	6 (35.3)	
Vision change after high-dose brolucizumab	
 Loss (≥ 10 letters lost)	1 (5.9)	
 Stable (< 10 letters gained/lost)	14 (82.4)	
 Gain (≥ 10 letters gained)	2 (11.8)	
Treatment interval, week	
 Prior agent before switching to brolucizumab	7.2 ± 2.4	
 Standard-dose brolucizumab before increasing dose	10.2 ± 2.2	
 High-dose brolucizumab at 12 months	13.5 ± 2.8	
Extension of ≥ 2 weeks	
 After switching to standard-dose brolucizumab	13 (76.5)	
 After switching to high-dose brolucizumab	6 (35.3)	
Values are presented as mean ± standard deviation or as n (%)

In total, anterior uveitis occurred in one eye during standard-dose brolucizumab treatment and in another eye during high-dose brolucizumab treatment. There were no cases of retinal vasculitis, vascular occlusion, endophthalmitis, or vitreous opacity observed in any of the eyes.

Discussion

In patients with refractory AMD unresponsive to previous anti-VEGF therapies, switching to a standard dose of brolucizumab resulted in significant improvements in visual acuity and extended treatment intervals. Additionally, for patients experiencing reduced responses to the standard dose, escalating to the high dose effectively preserved visual acuity, central subfield thickness, and treatment intervals. Of note, high-dose brolucizumab treatment significantly decreased the occurrence of subretinal fluid and serous pigment epithelial detachment. There were no instances of severe intraocular inflammation following the transition for standard to high-dose treatment.

Recently, several studies have investigated the effect of switching from other anti-VEGF agents to standard-dose brolucizumab in patients with AMD. Abdin et al. reported that switching to brolucizumab led to a reduction in injections over one year, as well as decreases in subretinal fluid, pigment epithelial detachment, and macular thickness, without severe ocular inflammation [22]. Similarly, Ueda-Consolvo et al. observed that switching from aflibercept to brolucizumab in patients with type 1 MNV and PCV extended the treatment interval over 18 months [23]. In addition, Yeom et al. observed improvements not only in anatomical outcomes but also in visual acuity 1 year after switching to brolucizumab from other anti-VEGF agents [15]. However, they reported a poor response to standard-dose brolucizumab in 17.3% of the cases.

The challenge of achieving adequate responses despite monthly injections and managing suboptimal outcomes when extending treatment intervals is a common issue for clinicians and patients [24]. In our approach, we adjusted treatment for patients unresponsive to standard-dose brolucizumab by increasing rather than decreasing the dosage. Previous studies have indicated the efficacy of high-dose anti-VEGF therapy. The HARBOR trial suggested a marginal increase in durability with ranibizumab 2 mg compared to 0.5 mg in patients with treatment-naïve AMD, albeit without corresponding improvements in visual or anatomic outcomes [12]. Conversely, findings from the SAVE trial demonstrated that high-dose ranibizumab (2.0 mg) significantly enhanced visual acuity and anatomical outcomes in recalcitrant AMD in cases unresponsive to monthly ranibizumab or bevacizumab treatments [13]. Similarly, Nielsen et al. reported positive outcomes in refractory AMD patients with high-dose aflibercept (3.0 or 4.0 mg), including improvements in visual acuity, anatomical metrics, and extension of treatment intervals without an increase in intraocular pressure [24]. Broadhead et al. further supported these findings by showing that using high-dose anti-VEGF agents (3 mg aflibercept, 0.75 mg or 1.0 mg ranibizumab, and 1.8 mg or 2.5 mg bevacizumab) effectively maintained vision, improved anatomical outcomes, and enabled longer treatment intervals in patients with recalcitrant AMD without inducing high intraocular pressure [25].

The mechanism underlying the efficacy of high-dose anti-VEGF therapy remains unclear. A recent study reported that intravitreal aflibercept 8 mg extended the treatment interval in AMD patients by increasing the molar dose [26]. Some patients might require a higher concentration of VEGF blockade to achieve disease quiescence or experience more rapid clearance of the anti-VEGF drug from their vitreous cavity [13]. Nevertheless, given the ongoing debate regarding the optimal treatment approach due to the association of anti-VEGF therapy with macular atrophy [27], further long-term studies on high-dose anti-VEGF therapy are necessary.

Our study represents a retrospective analysis conducted on a limited number of patients, and the variability in prior treatments among them limits the generalizability of our findings. Due to the absence of a control group that maintained or reduced the treatment interval with standard-dose brolucizumab for refractory AMD, it is challenging to completely exclude the possibility that our results may be related to regression to the mean or time effects [28]. Nonetheless, our study provides insights into the effectiveness of both standard-dose and high-dose brolucizumab in real-world clinical settings. Considering the occasional occurrence of severe ocular inflammation, such as retinal vasculitis or vascular occlusion, associated with brolucizumab, it is crucial not to overlook its adverse effects [29]. However, the absence of severe ocular adverse events following dose escalation of brolucizumab in our study suggests that our approach may offer benefits for patients with refractory AMD in clinical practice, potentially leading to future socioeconomic cost reductions. Further research using a prospective design and large sample sizes is warranted, not only on brolucizumab but also on other anti-VEGF agents, to compare the efficacy, safety, and socioeconomic outcomes of dose escalation with both shortening or maintaining the treatment interval with the standard dose and switching between anti-VEGF agents.

Conclusions

In summary, high-dose brolucizumab was found to be effective in patients who had previously shown no response to standard-dose brolucizumab after switching from prior anti-VEGF agents. Increasing the dosage of brolucizumab could emerge as a viable treatment option, providing sustained disease control and alleviating treatment burden for patient with refractory AMD.

Acknowledgements

We thank all study participants for their involvement in the study.

Authorship

All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given their approval for this version to be published.

Author Contributions

Jinsoo Kim: Conceptualization, investigation, methodology, writing—original draft, review and editing. Min Seon Park: Investigation. Bum-Joo Cho: Investigation. Soonil Kwon: Methodology, Writing—review and editing.

Funding

No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Jinsoo Kim, Min Seon Park, Bum-Joo Cho, and Soonil Kwon have nothing to disclose.

Ethical Approval

The study was approved by the Institutional Review Board of Hallym University Sacred Heart Hospital (IRB No. Hallym 2024-06-003), and informed consent was waived due to the retrospective nature of the chart review study. The study adhered to the tenets of the Declaration of Helsinki.
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