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Clinical Outcomes of Switching to Brolucizumab in Refractory Polypoidal Choroidal Vasculopathy Treated with Aflibercept
J Retin 2024;9(2):156-161
Published online November 30, 2024
© 2024 The Korean Retina Society.

Seung Chul Baek1,2, Areum Jeong1,2, Min Sagong1,2

1Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Korea
2Yeungnam Eye Center, Yeungnam University Hospital, Daegu, Korea
Correspondence to: Min Sagong, MD, PhD
Department of Ophthalmology, Yeungnam University College of Medicine, #170 Hyunchung-ro, Nam-gu, Daegu 42415, Korea
Tel: 82-53-620-3443, Fax: 82-53-626-5936
E-mail: msagong@yu.ac.kr
Received October 2, 2024; Revised October 6, 2024; Accepted October 9, 2024.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Purpose: In the present study, the efficacy and safety of brolucizumab in refractory polypoidal choroidal vasculopathy (PCV) patients treated with aflibercept were investigated.
Methods: The medical records of patients with refractory PCV treated with aflibercept were reviewed. All patients had subretinal fluid or intraretinal fluid followed by at least three consecutive injections of aflibercept on a 4–8-week dosing schedule before switching to brolucizumab. Changes in injection intervals, optical coherence tomography (OCT), and OCT angiography parameters including central macular thickness (CMT), subfoveal choroidal thickness (SFCT), polyp height, lesion area, flow density, and polyp regression rate were evaluated before and 6 months after switching to brolucizumab.
Results: The study included 32 eyes of 32 patients with PCV who received brolucizumab injections as switch therapy and were followed at 6 months. After switching to brolucizumab, 53% of eyes had dry macula and the injection interval was extended from 5.4 ± 1.7 weeks to 10.8 ± 2.9 weeks. Best-corrected visual acuity remained stable over the 6 months (p = 0.166). CMT and SFCT were reduced at 6 months after switching to brolucizumab (p = 0.042 and p = 0.023, respectively). Polyp regression was complete in 12.5% and partial in 62.5% of eyes. The largest polyp height and lesion size significantly decreased (p = 0.035 and p = 0.010, respectively). However, significant difference was not found regarding flow density after switching to brolucizumab (p = 0.145). Intraocular inflammation-related adverse events were not reported.
Conclusions: Brolucizumab could provide additional benefits in refractory PCV treated with aflibercept by reducing leakage from polyps, branching vascular networks, and choroid.
Keywords : Aflibercept; Brolucizumab; Choroidal thickness; Polypoidal choroidal vasculopathy
Introduction

Polypoidal choroidal vasculopathy (PCV) is a distinct subtype of neovascular age-related macular degeneration (AMD) that is particularly prevalent in Asian populations. Characterized by the presence of polypoidal lesions and abnormal branching vascular networks in the choroid, PCV often leads to recurrent subretinal hemorrhage, fluid accumulation, and, ultimately, significant vision loss if left untreated [1-3]. The mainstay of PCV treatment has been anti-vascular endothelial growth factor (anti-VEGF) therapy with aflibercept, a widely used agent due to its dual inhibition of VEGF-A and placental growth factor. However, a substantial number of PCV patients exhibit suboptimal responses to aflibercept, with persistent or recurrent fluid, hemorrhage, or polypoidal activity, and classified as refractory PCV [4,5].

Refractory PCV remains a significant therapeutic challenge because responsiveness to repeated intravitreal anti-VEGF injections is often limited. This issue demands the exploration of alternative therapeutic options to effectively manage this condition and prevent further vision deterioration. In this context, brolucizumab has emerged as a promising treatment option. Brolucizumab is a single-chain antibody fragment that offers higher molar doses per injection, enhanced tissue penetration, and longer duration of action compared with previous anti-VEGF agents [6]. These properties indicate brolucizumab could provide more robust suppression of VEGF activity. In recent studies, the potential of brolucizumab to achieve significant reductions in retinal fluid, choroidal thickness, and polypoidal lesion in patients with PCV have been emphasized [5,7,8]. However, the efficacy, specifically in aflibercept-refractory PCV patients, remains less well-defined. Therefore, the efficacy and safety of brolucizumab in patients with PCV refractory to aflibercept treatment were evaluated in the present study.

Materials and Methods

This study received approval from the Institutional Review Board (IRB) of Yeungnam University Hospital and adhered to the tenets of the Declaration of Helsinki (IRB No: 2024-09-039). Due to the retrospective nature of the study and the use of anonymized data, the IRB of Yeungnam University Hospital waived the need for informed consent. A retrospective chart review of consecutive patients over 50 years of age diagnosed with PCV between March 2021 and March 2023 was performed. Patients who had refractory PCV with subfoveal lesions that showed unresponsiveness to aflibercept and underwent brolucizumab injections were included. All patients showed persistent fluid on optical coherence tomography (OCT) after at least three consecutive aflibercept injections on a dosing schedule of 4–8 weeks before switching to brolucizumab and underwent more than 6 months of follow-up after the first brolucizumab injection. The exclusion criteria were history of other retinal diseases including uveitis, diabetic retinopathy, epiretinal membrane, retinal detachment, glaucoma, refractive error exceeding ± 6 diopters, subretinal hemorrhage or fibrosis obscuring the structure on OCT and OCT angiography (OCTA), or a history of photodynamic therapy or vitreoretinal surgery. For each patient, demographic information such as age, gender, history of anti-VEGF injections, and comorbidities was collected.

The central macular thickness (CMT), subfoveal choroidal thickness (SFCT), and largest polyp height, fluid status (defined by presence of intraretinal fluid (IRF) and/or subretinal fluid (SRF), and/or pigment epithelial detachment on OCT scan (Spectralis OCT; Heidelberg Engineering) were measured at the initial visit, before, and 6 months after switching to brolucizumab. Complete regression of the polyp was defined as a case where the polyp completely disappeared on OCT, and partial regression was defined as a case where the polyp was reduced in size but remained [9]. CMT, SFCT, and largest polyp height were measured by two retinal specialists using the built-in OCT software. An average of two measurements was used for the analysis for each parameter. In addition, lesion area and flow density were measured using OCTA (Avanti; Optovue).

A paired t-test and the Wilcoxon signed-rank test were used to determine the significance of the difference between the values before and after switching to brolucizumab. Paired t-test was used for normally distributed data and the Wilcoxon signed-rank test was used for data that did not follow a normal distribution. A comparison of best-corrected visual acuity (BCVA), CMT, and SFCT at each time point was performed by repeated measures analysis of variance. Statistical Package for Social Sciences Version 20.0 (IBM Corp.) was used for statistical evaluation. A p-value < 0.05 was considered to indicate statistical significance.

Results

Demographics and clinical characteristics

The present study included 32 eyes of 32 patients with refractory PCV. The mean age of the population was 62.8 ± 7.4 years. The mean baseline BCVA was 0.48 ± 0.21 logMAR, mean CMT before switching to brolucizumab was 379.0 ± 129.6 μm, and mean SFCT before switching to brolucizumab was 290.2 ± 88.6 μm. The treatment history included a mean 36.0 ± 26.6 anti-VEGF injections per eye over a mean period of 83.4 ± 47.8 months. The mean injection interval before switching to brolucizumab was 5.4 ± 1.7 weeks. The last injection interval was 4 weeks for 20 patients and 8 weeks for 12 patients. Table 1 shows the baseline characteristics of the enrolled patients.

Demographics and clinical characteristics when switching to brolucizumab

Characteristic Value (n = 32)
Age (years) 62.8 ± 7.4
Gender (male:female) 13:19
Best-corrected visual acuity (logMAR) 0.48 ± 0.21
Time from diagnosis to first brolucizumab (months) 83.4 ± 47.8
Injection number before switching 36.0 ± 26.6
Injection interval before switching (weeks) 5.4 ± 1.7
Last injection interval before switching (4 weeks:8 weeks) 20:12
Central macular thickness (μm) 379.0 ± 129.6
Subfoveal choroidal thickness (μm) 290.2 ± 88.6
Choriocapillaris/Sattler layer (μm) 84.4 ± 13.1
Haller layer (μm) 204.3 ± 35.4
Fluid compartments
Intraretinal fluid 5 (15.6)
Subretinal fluid 31 (96.8)
Pigment epithelial detachment 9 (28.1)
Number of polyps 2.45 ± 0.67

Values are presented as mean ± standard deviation, number only, or number (%).



Clinical outcomes of brolucizumab treatment

Following the first brolucizumab injection, the mean follow-up period was 26.6 weeks. During this period, an average of 2.7 intravitreal brolucizumab injections were administered at 10.8 ± 2.9-week intervals. A dry macula was achieved in 18 eyes (56.3%) at 6 months. Complete polyp regression was observed in 4 eyes (12.5%) and partial regression was observed in 20 eyes (62.5%) at 6 months. Eight eyes (25.0%) showed no polyp regression. BCVA showed a significant improvement after aflibercept treatment compared with the initial visit (0.67 ± 0.24 logMAR to 0.48 ± 0.21 logMAR, p < 0.001). However, a significant difference in BCVA measurements was not observed between before and 6 months after switching to brolucizumab (p = 0.166). CMT significantly decreased from the initial visit to before switching to brolucizumab (414.8 ± 140.4 μm to 379.0 ± 129.6 μm, p < 0.001) and further reduced at 6 months after brolucizumab treatment, showing a significant difference between before and 6 months after switching to brolucizumab (p = 0.042). SFCT and Haller layer thickness significantly decreased from the initial visit to before switching to brolucizumab (p = 0.002 and p = 0.012, respectively). The SFCT further decreased at 6 months after brolucizumab treatment, showing a significant difference between before and 6 months after switching to brolucizumab (290.2 ± 88.6 μm to 261.6 ± 72.9 μm, p = 0.023). Haller layer thickness also significantly reduced at 6 months after switching to brolucizumab (204.3 ± 35.4 μm to 180.8 ± 31.9 μm, p = 0.020). Furthermore, both largest polyp height and lesion area significantly decreased after aflibercept treatment when compared with the initial visit (p = 0.014 and p < 0.001, respectively). Largest polyp height and lesion area further decreased 6 months after switching to brolucizumab (p = 0.035 and p = 0.010, respectively; Table 2).

Clinical outcomes before and at 6 months after switching to brolucizumab in refractory polypoidal choroidal vasculopathy patients treated with aflibercept

Variables Initial visit Pre-brolucizumab Post-brolucizumab p-value (Initial visit vs. pre-brolucizumab) p-value (Pre-brolucizumab vs. Post-brolucizumab)
BCVA (logMAR) 0.67 ± 0.24 0.48 ± 0.21 0.38 ± 0.19 <0.001 0.166
CMT (μm) 414.8 ± 140.4 379.0 ± 129.6 356.5 ± 116.8 <0.001 0.042
Subfoveal choroidal thickness (μm) 316.5 ± 93.7 290.2 ± 88.6 261.6 ± 72.9 0.002 0.023
Choriocapillaris/Sattler layer (μm) 86.2 ± 12.8 84.4 ± 13.1 80.6 ± 10.7 0.471 0.252
Haller layer (μm) 228.3 ± 32.8 204.3 ± 35.4 180.8 ± 31.9 0.012 0.020
Largest polyp height 285.5 ± 168.2 256.0 ± 207.8 164.4 ± 113.4 0.014 0.035
Lesion area (mm2) 3.7 ± 2.3 3.5 ± 2.1 3.1 ± 1.7 <0.001 0.010
Flow density (%) 44.3 ± 10.2 45.6 ± 8.9 47.3 ± 9.2 0.204 0.145

Values are presented as mean ± standard deviation.

BCVA = best-corrected visual acuity; CMT = central macular thickness.



The changes in visual and anatomical outcomes over 6 months are shown in Fig. 1. The BCVA tended to improve substantially but without statistical significance. CMT, SFCT, and Haller layer thickness showed consistent decreases throughout the treatment period. Choriocapillaris/Sattler layer thickness showed a tendency to decrease but was not statistically significant (Fig. 1).

Fig. 1. Changes in visual and anatomic outcomes of polypoidal choroidal vasculopathy eyes before and after switching to brolucizumab. Repeated-measures ANOVA was performed to compare the values of best-corrected visual acuity (BCVA, A), central macular thickness (CMT, B), subfoveal choroidal thickness (C), choriocapillaris (CC)/Sattler layer thickness (D), and Haller layer thickness (E) at 1, 3, and 6 months with baseline values. ANOVA = analysis of variance.

Six months after switching to brolucizumab, 56.2% (18 of 32) of eyes with any fluid achieved complete absorption and fluid reduction was observed in 25% of cases. In particular, 59% of eyes with SRF and 44% of eyes with IRF experienced complete fluid absorption. Unchanged fluid levels were observed in 15.6% (5 of 32) of eyes and worsening of fluid status was observed in only 1 eye (Fig. 2).

Fig. 2. Fluid status 6 months after switching to brolucizumab in polypoidal choroidal vasculopathy eyes refractory to repeated aflibercept injections. SRF = subretinal fluid; IRF = intraretinal fluid.

Retinal pigment epithelium tears, intraocular inflammation, retinal vasculitis, or vascular obstruction did not occur.

Discussion

The results of this study demonstrated that switching to brolucizumab in patients with refractory PCV who were previously treated with aflibercept can lead to significant anatomical improvements. Specifically, the significant reductions in CMT, SFCT, Haller layer thickness, and the size of polypoidal lesions emphasize the potential of brolucizumab as an effective therapeutic option for this challenging condition.

A major finding was the substantial extension of injection intervals from 5.4 to 10.8 weeks, indicating that brolucizumab could effectively reduce the treatment burden while maintaining vision and anatomical stability in refractory PCV cases. The polyp regression rate of PCV patients has been reported to vary depending on treatment method. In the EVEREST II study, complete regression of 69.3% in the ranibizumab and photodynamic therapy combination group and 34.7% in the ranibizumab monotherapy group was reported [10]. In the PLANET study, a complete polyp regression rate of 38.9% after aflibercept monotherapy was reported [11]. In a recent study in which 17 treatment-naïve eyes with PCV were treated with brolucizumab alone, a complete polyp regression rate of 93.3% at 1 year was reported [12]. In the present study, a favorable polyp regression rate was also observed, with 75% of eyes showing complete or partial regression 6 months after switching to brolucizumab. The largest polyp height and lesion area also decreased, showing the anatomic benefits of brolucizumab.

Brolucizumab is a single-chain antibody fragment with a smaller molecular size than other anti-VEGF agents. The smaller molecular size of brolucizumab provides for potentially more effective penetration of the retina and choroid, improving its effectiveness in reducing retinal and subretinal fluid accumulation. In several studies, reduction of choroidal thickness was observed after brolucizumab treatment in patients with neovascular AMD [13-16]. In the present study, CMT, SFCT, and Haller layer thickness also significantly decreased even in patients who were refractory to aflibercept. However, the effects of choroidal thickness reduction on prognosis remain uncertain. Koizumi et al. found a reduction in choroidal thickness was associated with better visual outcomes following aflibercept treatment [17]. Conversely, Sadda et al. [18] reported a thinner choroid may increase the risk of macular atrophy. Further research is required to clarify the long-term implications of choroidal thickness changes following brolucizumab therapy in PCV. Despite the favorable anatomic outcomes, mean BCVA did not significantly improve after switching to brolucizumab possibly because patients had already undergone multiple anti-VEGF treatments, potentially reducing the likelihood of further visual acuity improvements.

The present study had several limitations that should be acknowledged. First, the sample size was relatively small, limiting the generalizability of the findings to a broader population of patients with refractory PCV. Larger, multicenter studies are necessary to confirm these results and ensure their applicability in diverse clinical settings. Second, the follow-up period was relatively short, which restricts the ability to assess the long-term efficacy and safety of brolucizumab in this population. A third limitation lies in the retrospective nature of the study, which may influence the data collection and interpretation. A prospective, randomized controlled trial could provide stronger evidence regarding the comparative effectiveness of brolucizumab in refractory PCV. Fourth, the polyp regression was defined based on OCT rather than indocyanine green angiography (ICGA) because ICGA was not available 6 months after switching. Although the results of the study showed significant anatomical improvements, functional outcomes such as visual acuity improvement may be influenced by various confounding factors, including baseline disease severity and prior treatment response, which were not fully controlled in this analysis.

In conclusion, switching to brolucizumab in patients with aflibercept-refractory PCV resulted in significant improvements in anatomical outcomes, with an extended injection interval and no reported serious safety concerns. These findings support the use of brolucizumab as a viable treatment option in refractory cases, particularly in subjects who require more durable VEGF suppression. Future studies with longer follow-up periods are warranted to further assess the long-term efficacy and safety of this treatment.

Conflicts of Interest

Min Sagong reported being a consultant for and receiving grant support from Samsung Bioepis, Novartis, Bayer, Roche, Allergan/Abbvie, Celltrion, Alteogen, Alcon and Curacle, and receiving lecture fee from Novartis, Bayer, Roche, and Allergan/Abbvie. Seung Chul Baek and Areum Jeong declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author Contribution

Conception (M.S.); Design (M.S); Data acquisition (S.C.B.); Analysis (S.C.B., A.J.); Interpretation (M.S., A.J.); Writing (S.C.B., A.J.); Review (M.S., A.J.); Final approval of the article (All authors)

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