Abstract
Brolucizumab is a second-generation vascular endothelial growth factor (VEGF) inhibitor. To date, there have been no reports comparing treatment outcomes between exudative age-related macular degeneration with or without the pachychoroid phenotype using a second-generation VEGF inhibitor. The present study compared two-year as-needed brolucizumab treatment outcomes in patients with and without pachychoroid phenotypes. Sixty-six eyes completed two years of follow-up, and 14 and 52 eyes were classified into the pachychoroid and non-pachychoroid phenotypes, respectively. At 24 months, best-corrected visual acuity (BCVA) significantly improved in both groups, from 0.30 ± 0.29 to 0.12 ± 0.21 in the pachychoroid phenotype and 0.43 ± 0.36 to 0.31 ± 0.37 in the non-pachychoroid phenotype (p = 0.014 and 0.0013, respectively). At the 24-month follow-up, there were significantly fewer eyes requiring retreatment in the pachychoroid phenotype than in the non-pachychoroid phenotype (50% vs. 83%, p = 0.03). Although the number of additional injections was comparable between the two groups in the first 12 months (1.2 ± 1.4 vs. 1.7 ± 1.6, p = 0.29), the number of additional injections was significantly lower in the pachychoroid phenotype than in the non-pachychoroid phenotype (1.5 ± 2.4 vs. 3.2 ± 2.6, p = 0.0098) in the second 12 months. In the 24-month as-needed brolucizumab treatment group, the response to the pachychoroid phenotype was favorable, with significant BCVA improvement and fewer additional injections, particularly in the second 12 months.
Keywords: Exudative age-related macular degeneration, Two-year outcomes, Brolucizumab, Aflibercept, Choroidal vascular hyperpermeability, Recurrence
Subject terms: Diseases, Medical research
Introduction
Age-related macular degeneration (AMD) is a leading cause of severe vision loss in developed countries. It is estimated to affect 288 million people worldwide by 20401. Depending on the size of the drusen, they were classified into early or intermediate stages. In addition to this classification, the advanced stage is defined as atrophy or macular neovascularization (MNV), and MNV subtypes vary depending on the drusen subtypes2. In 2013, the concept of “pachychoroid” was proposed3, and the differences in clinical characteristics and treatment outcomes between AMD with or without pachychoroid phenotypes were investigated.
Vascular endothelial growth factor (VEGF) is critical for developing MNV4. VEGF inhibitors have been established as treatments for MNV secondary to AMD. Brolucizumab was the 4th commercially available VEGF inhibitor following pegaptanib, ranibizumab, and aflibercept 2 mg, and is called “the second-generation VEGF inhibitor” along with faricimab and aflibercept 8 mg because it could prolong the treatment interval and reduce the burden of both patients and physicians5–7.
In the HAWK/HARRIER trial, the treatment interval was maintained at 12 weeks in 40–45% of patients at 96 weeks, with maintained best-corrected visual acuity (BCVA)8. Exudation was less frequently observed in the brolucizumab-treated group than in the aflibercept-treated group. In the real world, a few studies have investigated the 2-year results of brolucizumab in exudative AMD9,10, however, there have been no reports comparing the treatment outcomes in eyes with or without the pachychoroid phenotype using a second-generation VEGF inhibitor.
The present study compared the two-year outcomes of an as-needed brolucizumab regimen for exudative AMD with and without the pachychoroid phenotype.
Results
During the study period, all exudative AMD other than retinal angiomatous proliferation were treated with 3 monthly brolucizumab injections with as-needed additional injections, and 66 eyes of 66 patients completed the 2-year follow-up period. Fourteen and fifty-two eyes were classified as having pachychoroid and non-pachychoroid phenotypes, respectively. Table 1 shows the baseline characteristics of the participants. This study did not include eyes with retinal angiomatous proliferation.
Table 1.
Baseline demographic and clinical characteristics of patients with age-related macular degeneration between the 2 groups.
| Pachychoroid phenotype (n = 14) |
Non-Pachychoroid phenotype (n = 52) |
P-value | |
|---|---|---|---|
| Age (years) | 70.6 ± 6.0 | 76.1 ± 8.9 | 0.011 |
| Male | 11 (78.6%) | 38 (73.1%) | 0.94 |
|
Mean baseline log MAR BCVA |
0.30 ± 0.29 | 0.43 ± 0.36 | 0.22 |
|
Baseline Central retinal thickness (µm) |
241 ± 74 | 403 ± 224 | 3.3 × 10− 4 |
|
Baseline subfoveal choroidal thickness (µm) |
295 ± 67 | 179 ± 72 | 2.6 × 10− 5 |
| Greatest linear dimension(µm) | 2562 ± 1986 | 3242 ± 2069 | 0.22 |
| Type1 MNV/Type2 MNV/PCV | 7/ 2 /5 | 21/6/25 | 0.71 |
One patient developed intraocular inflammation after the third injection. Mild inflammation was seen in the anterior chamber, and the inflammation resolved after the topical dexamethasone. This case did not require additional injection during the maintenance phase. In 66 eyes, 30 (45%) and 36 (55%) eyes were polypoidal choroidal vasculopathy and neovascular AMD, respectively. Patients with the pachychoroid phenotype were significantly younger and had a significantly thicker choroid and thinner central retina than patients with the non-pachychoroid phenotype. Figure 1 shows the changes in best-corrected visual acuity (BCVA), subfoveal choroidal thickness, central retinal thickness according to the phenotype and change of BCVA in eyes with type 1 MNV or type 2 MNV. BCVA significantly improved at 6,9,12,18, and 24 months compared to the baseline BCVA in the pachychoroid phenotype. In the non-pachychoroid phenotype, BCVA significantly improved at 3,6,9,12,18, and 24 months.
Fig. 1.
Change of best-corrected visual acuity (BCVA), subfoveal choroidal thickness (SCT), and central retinal thickness (CRT) during the 24 months. (a) Change of BCVA according to phenotypes. In the pachychoroid phenotype, BCVA significantly improved from 0.30 ± 0.29 to 0.19 ± 0.29, 0.13 ± 0.22, 0.12 ± 0.21, 0.15 ± 0.20, 0.14 ± 0.20, and 0.12 ± 0.21 at 3, 6, 9, 12, 18, and 24 months, respectively (p = 0.11, 0.010, 0.011, 0.014, 0.017, and 0.014). In the non-pachychoroid phenotype, BCVA also improved significantly from 0.43 ± 0.36 to 0.34 ± 0.31, 0.34 ± 0.34,0.32 ± 0.33, 0.32 ± 0.36, 0.31 ± 0.36, and 0.31 ± 0.37 at 3, 6, 9, 12, 18, and 24 months, respectively (p = 0.0073, 0.0031, 0.0025, 0.00079, 0.00043, and 0.0013). (b) Change of SCT according to phenotypes. In the pachychoroid phenotype, SCT significantly decreased from 295 ± 69 to 255 ± 76, 270 ± 79, 284 ± 86, 266 ± 82, and 270 ± 92 at 3, 6, 12, 18, and 24 months, respectively (p = 0.0019, 0.013, 0.36, 0.023, and 0.052). In the non-pachychoroid phenotype, SCT significantly decreased from 179 ± 73 to 147 ± 57, 154 ± 64, 152 ± 62, 154 ± 67, and 151 ± 60 at 3, 6, 12, 18, and 24 months, respectively (p = 3.0 × 10− 7, 2.4 × 10− 6, 3.7 × 10− 6, 1.6 × 10− 5, and 8.3 × 10− 6). (c) Change of CRT according to phenotypes. In the pachychoroid phenotype, CRT significantly decreased from 241 ± 71 to 179 ± 53, 189 ± 69, 174 ± 37, 173 ± 43, and 183 ± 56 at 3, 6,12,18 and 24 months, respectively (p = 0.0037, 0.022, 0.00098, 0.0019, and 0.0092). In the non-pachychoroid phenotype, CRT significantly decreased from 403 ± 226 to 202 ± 98, 230 ± 106, 240 ± 142, 230 ± 90, and 228 ± 72 at 3, 6, 12, 18, and 24 months, respectively (p = 4.2 × 10− 10, 3.8 × 10− 9, 8.9 × 10− 9, 6.6 × 10− 9, and 2.5 × 10− 9). (d) Change of BCVA in eyes with type 1 macular neovascularization (MNV) or type2 MNV. In 28 eyes with type 1 MNV, BCVA improved from 0.43 ± 0.28 to 0.39 ± 0.31, 0.38 ± 0.33, 0.36 ± 0.31, 0.36 ± 0.30, 0.33 ± 0.27, and 0.34 ± 0.28 at 3, 6, 9, 12, 18, and 24 months, respectively (p = 0.42, 0.17, 0.10, 0.043, 0.0086, and 0.044. In 8 eyes with type 2 MNV, BCVA improved from 0.82 ± 0.46 to 0.47 ± 0.32, 0.46 ± 0.30, 0.35 ± 0.31, 0.38 ± 0.30, 0.36 ± 0.30, and 0.38 ± 0.37 at 3, 6, 9, 12, 18, and 24 months, respectively (p = 0.058, 0.043, 0.017, 0.012, 0.018, and 0.043).
During the 24-month follow-up, the total number of additional injections was 4.5 ± 4.0, composed of 1.6 ± 1.6 and 2.9 ± 2.6 in the first 12 months and the second 12 months, respectively. Table 2 compares the retreatment-free proportion and number of additional injections according to phenotype. In the first 12 months, the number of additional injections was comparable between the two groups (1.2 ± 1.4 vs. 1.7 ± 1.6, p = 0.29, Mann–Whitney U test). However, in the second 12 months, the number of additional injections was significantly lower in the pachychoroid phenotypes than in the non-pachychoroid phenotypes (1.5 ± 2.4 vs. 3.2 ± 2.6, p = 9.8 × 10− 3, Mann–Whitney U test). Figure 2 shows the distribution of additional injections according to the phenotype. In the first 12 months, the two groups’ distribution patterns of additional injections were comparable. In the second 12 months, the number of eyes requiring additional injections was significantly lower in the pachychoroid phenotype than in the non-pachychoroid phenotype (43% vs. 83%, p = 0.005, chi-square test). Figure 3 (a) shows the Kaplan–Meier survival curve for the retreatment-free proportion after the loading phase in all 66 eyes; 24 (36%) and 16 (24%) eyes did not require additional injections at 12 and 24 months, respectively. Figure 3 (b) shows the Kaplan–Meier survival curve comparing the two groups; it did not reach statistical significance (p = 0.072, log-rank test) regarding the retreatment-free proportion between the two groups. During the study period, no eyes received initial PDT, and no eyes receiving brolucizumab treatment were switched to PDT.
Table 2.
Number of additional injections and retreatment-free proportion.
| Pachychoroid phenotype (n = 14) |
Non-Pachychoroid phenotype (n = 52) |
P-value | |
|---|---|---|---|
|
Number of additional injections (3–12 months) |
1.2 ± 1.4 | 1.7 ± 1.6 | 0.29 |
|
Number of additional injections (13–24 months) |
1.5 ± 2.4 | 3.2 ± 2.6 | 0.0098 |
|
Total number of additional injections (3–24 months) |
2.7 ± 3.6 | 4.9 ± 3.9 | 0.04 |
|
The first 12-month retreatment-free proportion |
7 (50%) | 17 (32.7%) | 0.38 |
|
24-month retreatment-free proportion |
7 (50%) | 9 (17.3%) | 0.03 |
Fig. 2.
Distribution of the number of additional injections according to phenotypes. (a) In the first 12 months, the number of additional injections of 0, 1, 2, 3, and 4 were 50%, 7.1%, 21.5%, 14.3%, and 7.1%, respectively, in the pachychoroid phenotype. The number of additional injections of 0, 1, 2, 3, 4, and 5 were 32.7%, 21.2%, 13.5%, 13.5%, 13.5%, and 5.8%, respectively, in the non-pachychoroid phenotype. (b) In the second 12 months, the number of additional injections at 0, 1, 2, 3, 6, and 8 were 57.3%, 14.3%, 7.1%, 7.1%, 7.1%, and 7.1%, respectively, in the pachychoroid phenotype. The numbers of additional injections at 0, 1, 2, 3, 4, 5, 6, 7, 9, and 12 were 17.3%, 11.5%, 15.4%, 15.4%, 7.7%, 15.4%, 9.6%, 3.8%, 1.9%, and 1.9%, respectively, in the non-pachychoroid phenotype.
Fig. 3.
Kaplan–Meier survival curve associated with the retreatment-free proportion after three monthly loading administrations. (a) In all 66 eyes, the retreatment-free proportions were 36% and 24% at 12 and 24 months, respectively. (b) In the pachychoroid phenotype, the retreatment-free proportion was 50% at 12 and 24 months. For the non-pachychoroid phenotype, the retreatment-free proportions were 32.7% and 17.3% at 12 months and 24 months, respectively. There was no statistically significant difference between the two groups (p = 0.07, log-rank test).
Discussion
The present study compared two-year as-needed brolucizumab treatment outcomes of patients with exudative AMD with and without pachychoroid phenotypes. During the 24-month follow-up, the response to the pachychoroid phenotype was favorable, with fewer additional injections compared to the non-pachychoroid phenotypes.
HAWK/HARRIER reported 96-week outcomes and eye continuing 12-week interval treatment was 45.4% and 38.6% in HAWK and HARRIER at the 96-week visit, respectively8. As these trials’ treatment intervals were 12 weeks at most, this indicated that all participants received at least seven additional injections during the 96-week follow-up period. In general, the number of additional injections is likely to be lower in the PRN regimen than in proactive treatment regimens, such as the treat-and-extend (T&E) regimen. The number of visits was higher in the PRN regimen than in the T&E regimen. Therefore, the visual outcomes are likely to be poorer with the PRN regimen than with the T&E regimen. In the present study, visual improvement gained during the first 12 months was maintained until the 24-month visit in both the pachychoroid and non-pachychoroid phenotypes. This is probably because brolucizumab has a potentially sustained duration of action, greater tissue penetration, and therefore a strong effect on the resolution of exudation11. In the present study, the number of additional injections during the 24 months is 4.5 ± 4.0, far lower than the minimum number of additional injections (7 times) in the HARRIER/HAWK.
During the 24-month follow-up period, the retreatment-free proportions were 36% and 24% at 12 and 24 months, respectively. Few studies have investigated the retreatment-free proportions of PRN regimens using ranibizumab or aflibercept. Kuroda et al. reported that the retreatment-free proportions were 34.2% and 25.2% at 12 and 24 months using ranibizumab12, respectively, and other studies reported that the retreatment-free proportion were 34–36% and 15–25% at 12 and 24 months using aflibercept, respectively13–15. The retreatment-free proportion may be comparable irrespective of the type of VEGF inhibitor used.
In the present study, BCVA significantly improved at the 24-month visit in both groups .The retreatment-free proportion was significantly higher in the pachychoroid phenotype than in the non-pachychoroid phenotype (50% vs. 17.3%, p = 0.03), and the number of additional injections was significantly lower in the pachychoroid phenotype than in the non-pachychoroid phenotype (mean 2.7 vs. 4.9, median 0 vs. 4, p = 0.04). Matsumoto et al. compared the aflibercept response to type 1 macular neovascularization (MNV) with and without pachychoroid using the T&E regimen during a 2-year follow-up and reported that the number of injections was lower in type 1 MNV with pachychoroid and polypoidal lesions than in type 1 MNV without. They also reported that BCVA improvement was comparable between the two groups16. In general, the response to VEGF inhibitors in patients with pachychoroid phenotypes may be more effective in resolving exudation and prolonging the retreatment-free period. In the pachychoroid-driven AMD, the mechanism of MNV is considered the up-regulation of VEGF due to local and diffuse attenuation of choriocapillaris overlying dilated Haller’s layer. However, the VEGF level in the pachychoroid-driven AMD is reportedly lower than in drusen-driven AMD. With brolucizumab, the pathologically increased choroidal thickness and VEGF level might be easily normalized17. In the era of VEGF inhibitors, many physicians select a proactive treatment regimen, including treat-and-extend18,19. However, half of the eyes with pachychoroid phenotypes did not require additional injections during the study period. Therefore, PRN may be an appropriate treatment regimen for eyes with pachychoroid phenotypes to reduce the medical burden, costs, and risks associated with intravitreal injections. Recently, we investigated the remission rate of exudative AMD under a PRN regimen during a five-year follow-up, and the retreatment-free proportion in an initial 24-month and 60-month period was 24% and 11%, respectively16. Although the previous study did not differentiate pachychoroid and non-pachychoroid MNV, 16(24.2%) of 66 eyes achieved retreatment-free during the 24-month. Therefore, it is similar in terms of achieving the retreatment-free proportion between the aflibercept 2 mg and brolucizumab.
Photodynamic therapy with or without VEGF inhibitors is reportedly effective for pachychoroid neovasculopathy, including PCV; however, in some cases, recurrent exudation was repetitive. Repetitive PDT possibly induced choroidal ischemia, leading to visual deterioration. Brolucizumab could be one of the treatment options in eyes with pachychoroid neovasculopathy. Because the equivalent molecular dose of brolucizumab was approximately 10 times greater than that of aflibercept12, it is expected that brolucizumab could prolong the treatment interval and reduce the number of injections.
This study had several limitations. A major limitation was the retrospective nature of the analysis. Second, BCVA was not measured using the ETDRS chart. Third, the sample size was relatively small, particularly for patients with the pachychoroid phenotype. A large-scale study is necessary to confirm or refute this conclusion. On the other hand, the strength of this study is that all patients were followed by the strict PRN regimen.
In conclusion, during the 24-month as-needed brolucizumab treatment, the response to the pachychoroid phenotype was favorable, with significant BCVA improvement and fewer additional injections compared with the non-pachychoroid phenotypes.
Methods
We retrospectively reviewed the medical records of consecutive patients with exudative AMD who initiated brolucizumab monotherapy between August 2020 and January 2023 and fulfilled the following four inclusion criteria: (1) treatment-naïve eyes with exudative AMD, (2) follow-up duration > 24 months, and (3) treatment regimen of three consecutive monthly intravitreal injections thereafter. The exclusion criteria were as follows: (1) maculopathy other than exudative AMD, (2) previous history of uveitis, and (3) surgical treatment, including vitrectomy.
This retrospective study was approved by the Institutional Review Board of the University of Yamanashi and conducted according to the tenets of the Declaration of Helsinki. Before treatment initiation, each patient provided written informed consent.
On the initial visit, all patients received comprehensive ophthalmic examinations including best-corrected visual acuity (BCVA) measurement using a Landolt chart, slit-lamp biomicroscopy with or without 78 diopter lens, intraocular measurements, color fundus photography, spectral domain and swept-source optical coherence tomography (SD-OCT, Spectralis HRA2, Heidelberg, Dossenheim, Germany) and (SS-OCT, DRI-OCT-1 Atlantis, Topcon, Japan), fluorescein/ indocyanine green angiography (FA/ ICGA) using a confocal scanning laser ophthalmoscope (Spectralis HRA2, Heidelberg, Dossenheim, Germany). All patients underwent comprehensive ophthalmic examinations except for FA/ICGA at every follow-up visit. The lesion size was measured as the greatest linear dimension covering dye leakage area, subretinal hemorrhage and pigment epithelial detachment, if present, using fluorescein angiography at baseline.
Treatment regimen
All patients received three consecutive monthly intravitreal brolucizumab (6.0 mg/0.05 ml), thereafter monthly follow-ups up to 24 months. If new bleeding was observed on color fundus photography, or recurrent exudation, including subretinal or intraretinal fluid, was detected on OCT, an additional single injection of brolucizumab (6.0 mg/0.05 ml) was administrated. All patients were followed up monthly. If recurrent exudation was not observed for > 12 months, the follow-up period was extended bimonthly.
Definition of pachychoroid phenotype
The pachychoroid phenotype was defined as the presence of choroidal vascular hyperpermeability during the late phase of ICGA. In addition, pachydrusen was defined as the presence of a pachychoroid phenotype irrespective of the ICGA results, as previously reported20. Two graders independently evaluated the presence or absence of the pachychoroid phenotype. Discordant grading was resolved by open arbitration. Figure 4 shows a representative case of the pachychoroid phenotype.
Fig. 4.
An 81-year-old male in the left eye with polypoidal choroidal vasculopathy and pachychoroid phenotype. (a) During the initial visit, color fundus photography revealed a subretinal hemorrhage (SRH) in the inferior temporal region of the left eye. (b) Indocyanine green angiography (ICGA) showed a polypoidal lesion and choroidal vascular hyperpermeability in the temporal fovea. (c) A retinal pigment epithelial protrusion corresponding to the polypoidal lesion was seen on OCT. (d) One month after the third injection, SRH was not apparent. (e) On the ICGA, the polypoidal lesion was resolved. (f) A retinal pigment epithelial protrusion was flattened at the lesion corresponding to the original polypoidal lesion on OCT.
Statistical analysis
Statistical analyses were performed using the DR. SPSS. The chi-square and the Mann–Whitney U tests were used to evaluate differences between categorical and continuous variables. Differences between baseline and post-treatment values were evaluated using the Wilcoxon signed-rank test. A log-rank test was performed to compare the period from baseline to the time requiring 1st additional injection in patients with and without pachychoroid phenotypes. Statistical significance was set at p < 0.05.
Author contributions
Y.F. Y.S. Y.K. and W.K. collected the data, Y.F., and Y.S. wrote the manuscript, Y.F. prepared Figs. 1, 2, 3 and 4, and all authors reviewed the manuscript.
Data availability
Our data cannot be shared openly to protect the participants’ privacy. Data is partially available from the corresponding author, Y.S., upon reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Our data cannot be shared openly to protect the participants’ privacy. Data is partially available from the corresponding author, Y.S., upon reasonable request.