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The aim of this study was to evaluate the real-world outcomes of brolucizumab use in Japanese patients with neovascular age-related macular degeneration (nAMD).
Methods
PHEASANT was a retrospective, multicenter, single-arm cohort study. The study included 438 patients, of whom 123 were treatment-naïve and 315 were pre-treated. The primary outcome was retinal fluid (subretinal fluid [SRF] and intraretinal fluid [IRF]) resolution at month 12, with change in visual and retinal anatomy parameters and safety assessed as key secondary outcomes.
Results
At baseline in the treatment-naïve cohort, 10.1% (n = 7/69) of patients were free of retinal fluid, increasing to 62.3% (n = 43/69) at month 12. In the pre-treated cohort, 14.9% (n = 30/201) of patients were free of retinal fluid at baseline, increasing to 43.8% (n = 88/201) at month 12. The median (interquartile range [IQR]) injection interval for pre-treated patients at month 12 was extended by 21 (7.0–35.0) days. The overall intraocular inflammation rate (including the rate of retinal vasculitis/retinal occlusive vasculitis of 0.46% [2/438]) was 8.4% (n = 37/438).
Conclusion
In a real-world clinical setting, brolucizumab was effective at drying the retina in treatment-naïve and pre-treated Japanese nAMD patients and therefore has the potential to reduce the treatment burden by prolonging injection intervals. Safety outcomes support the overall favorable benefit/risk profile of brolucizumab.
Prior Presentation: Data from this study were presented as part of an oral presentation by Professor Masayuki Ohnaka at the Japanese Ophthalmological Society congress, Thursday, April 6–Sunday, April 9, 2023.
Key Summary Points
There is a paucity of large, real-world, multicenter data analyses on the effectiveness and safety of brolucizumab in Japanese patients with neovascular age-related macular degeneration (nAMD).
This retrospective, multicenter, real-world study assessed the resolution of retinal fluid following brolucizumab use among Japanese nAMD patients, among other effectiveness and safety outcomes.
The study found that brolucizumab was effective at drying the retina in both treatment-naïve and pre-treated Japanese nAMD patients, while also demonstrating an overall favorable benefit/risk profile.
These results are in line with the phase III brolucizumab studies (HAWK and HARRIER), as well as other published brolucizumab data.
Brolucizumab was found to be effective at resolving retinal fluids and has the potential to reduce the treatment burden in Japanese nAMD patients.
Introduction
Neovascular age-related macular degeneration (nAMD), one of the leading causes of vision loss in the older population, is characterized by the exudation of fluid from abnormally growing blood vessels in the macula, leading to the accumulation of retinal fluid. The current standard of care for nAMD is intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents, which inhibit angiogenesis and help to prevent increased vascular permeability. Retinal fluid resolution is used both as an indicator of disease control and to guide the frequency of treatment because of the effectiveness of anti-VEGF therapy in reducing neovascularization-related exudation [1].
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Brolucizumab is a single-chain antibody fragment that rapidly penetrates the retina and inhibits all isoforms of VEGF-A [2]. The pivotal phase 3 HAWK and HARRIER trials on treatment-naïve nAMD patients demonstrated that anti-VEGF therapy with brolucizumab was non-inferior to aflibercept in visual acuity gains, with superior anatomical outcomes regarding retinal thickness reduction and fewer patients with retinal fluid after brolucizumab treatment at weeks 48 and 96 [3, 4]. The improvements in anatomical outcomes seen in HAWK and HARRIER have been confirmed in several subsequent real-world studies [5].
Brolucizumab is currently approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) (approved in May 2020) and many other health authorities globally, including the Food and Drug Administration (FDA) (approved in 2019) and the European Medicines Agency (EMA) (approved in 2020), for the treatment of nAMD. Of note, post-marketing reports of intraocular inflammation (IOI) in association with brolucizumab were first reported by the American Society of Retina Specialists (ASRS) in February 2020 [6]. An independent safety review committee (SRC), supported by Novartis Pharma AG, subsequently reported that the rate of definite/probable IOI in association with brolucizumab was 4.6% [7]. A recent analysis of data from the US Intelligent Research in Sight (IRIS) Registry, assessing safety outcomes in brolucizumab-treated nAMD patients, reported a similar incidence of IOI [8].
To date, a growing number of real-world studies report brolucizumab effectiveness, including an improvement in vision (particularly in treatment-naïve patients), reduction in retinal thickness, and reduction in retinal fluid—all biomarkers of disease activity in nAMD [5]. In terms of its impact on treatment burden, a large retrospective cohort study using German patient-level prescription data reported that patients who switched to brolucizumab had a median treatment interval extension of about 3 weeks at 12 months [9]. Similarly, a recent retrospective study of 482 nAMD eyes reported a mean (95% confidence interval [CI]) injection interval extension from baseline to month 12 of 26.9 (19.7, 34.0) days following a switch to brolucizumab [10].
Several clinical practices in Japan have reported on the effectiveness of brolucizumab in the real world, but the sample sizes are generally modest and are often from single centers [11‐16]. The aim of the PHEASANT study was to evaluate the real-world effectiveness and safety of brolucizumab in 438 Japanese treatment-naïve and pre-treated patients with nAMD. The primary objective of the study was to evaluate fluid resolution at month 12 after initiation of brolucizumab in routine practice. In addition, other visual, anatomical, and safety assessments, including the incidence of adverse events of special interest (AESIs), were recorded to provide information on the effectiveness/safety of brolucizumab.
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Methods
Study Design
PHEASANT was a retrospective, single-arm cohort study of nAMD patients in Japan treated with brolucizumab. The study included 438 patients, of which 123 were treatment-naïve (treatment-naïve patients were those who had not received any anti-VEGF therapy in the 12 months pre-index) and 315 were pre-treated (pre-treated patients were those who had received at least one other anti-VEGF therapy [ranibizumab, aflibercept, bevacizumab (off-label)] in the 12 months pre-index), with the index date defined as the date of their first brolucizumab injection. Patients were eligible for inclusion if they had a diagnosis of nAMD, they were ≥ 50 years old at the index date, and the date of their first brolucizumab injection (index date) occurred in the first 7 months of brolucizumab being used in routine care in Japan, i.e., between May 25, 2020, and Dec 31, 2020 (index period). The overall study period ran from May 25, 2019, to December 31, 2021, which included a 12-month pre-index period (to allow collection of 12 months of patient history) (Fig. 1). Exclusion criteria were as follows: treatment for retinal vein occlusion (RVO), diabetic macular edema (DME), or myopic choroidal neovascularization (mCNV) or diagnosis of diabetes-related macular degeneration in the 6 months pre-index; any active intra/periocular infection or any active IOI in the study eye at index; any contraindication for brolucizumab use or ineligibility for brolucizumab as per the label; treatment with ≥ 3 types of other anti-VEGF therapies pre-index; participation in brolucizumab post-marketing surveillance or in an interventional clinical trial in parallel.
Fig. 1
Study design. *May 25, 2020 was chosen as the start date of the baseline period as this was the date of brolucizumab launch in Japan
To address the needs of different follow-up periods foreseen in the analysis, five patient cohorts were defined. The cohorts (in which all patients met the inclusion and exclusion criteria) were defined as follows: Cohort 0 (no minimum follow-up period); Cohort 1 (minimum follow-up period of 3 months); Cohort 2 (minimum follow-up period of 6 months); Cohort 3 (minimum follow-up period of 9 months); Cohort 4 (minimum follow-up period of 12 months); Cohort 5 (minimum follow-up period of 18 months). The primary analysis was based on analysis of cohort 4 (cohort 4 included 327 patients in total [93 treatment-naïve patients and 234 pre-treated patients]). The decision of whether to administer loading doses and the frequency of monitoring visits and of injections were solely at the discretion of the treating clinician. However, it should be noted that the majority of participating centers used either a “treat and extend” or “pro re nata” treatment regimen. Only data for the first eye treated with brolucizumab were used, and the patient was the unit of analysis. This study complied with the tenets of the Declaration of Helsinki and was approved by an ethics committee at each study center [Kansai Medical University Hospital: 2021267; Toyama University: R2021136; University of Yamanashi Hospital: 2553; Yokohama City University: F220600027; Jichi Medical University: 22–034; Chofu Eye Clinic: LIN08548; Nihon University Hospital: 20,220,109; Gumna University Hospital: IRB2021-055(1946)]. Patient consent was obtained, and subsequently, retrospective data on the 438 patients were collected between January 1, 2022, and July 31, 2022, after the study period. Eight centers situated across seven prefectures and three regions of Japan participated in the PHEASANT study (Table S1).
Study Outcomes
Baseline assessments were taken on the index date, and we use the term “baseline” in the presentation of the study results. The primary outcome for this study was the percentage of all observed patients (regardless of retinal fluid status at baseline), by treatment history status (i.e., treatment-naïve or pre-treated), with fluid resolution (i.e., without subretinal fluid [SRF] and without intraretinal fluid [IRF]) at month 12. Secondary outcomes included the percentage of patients with resolution of individual retinal fluids (i.e., SRF, IRF, subretinal pigment epithelium [RPE] fluid) at month 12, by treatment history status (assessed in both patients with a specific fluid at baseline and without a specific fluid at baseline); time to SRF and IRF resolution among patients with SRF and IRF at baseline; change in visual acuity (VA) between baseline and month 12 (all patients); change in central subfield thickness (CSFT) between baseline and month 12 (all patients); distribution and change in brolucizumab injection intervals (defined as the last interval at the end of follow-up [e.g. 12 months] minus the last interval before switch); and the incidence of AESI associated with brolucizumab among all patient eyes., i.e. IOI, retinal vasculitis, retinal occlusive vasculitis, and endophthalmitis.
Data Sources and Data Collection
Retrospective data were collected via electronic case report form (eCRF) filled out via Medidata RAVE® software (Medidata®, NY, USA). nAMD diagnoses were based on records of patient history and/or on results of diagnostic procedures such as fluorescein angiography (FA), optical coherence tomography (OCT), and indocyanine green angiography (ICGA). Anatomical outcomes were based on OCT readings. Visual outcomes were based on quantitative (e.g., Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and/or qualitative VA assessments (e.g., counting fingers, hand motions). As part of routine practice, each participating investigator performed VA (preferably best-corrected VA) assessments, and to facilitate data analysis, decimal VA values were converted to the ETDRS equivalent letter scores. Treatment-related information was obtained from prescription records.
Statistical Analysis
Standard descriptive statistics were generated for all study outcomes. Where applicable, point estimates with corresponding two-sided 95% confidence intervals were calculated. Time-to-event outcomes were analyzed via Kaplan–Meier methods. No missing value imputations were performed, and results were reported only for complete cases (n), with n reported for each variable. All analyses were conducted using SAS software.
Results
Retrospective data collection from eight centers in Japan returned data from 438 nAMD patients treated with brolucizumab: 123 treatment-naïve patients and 315 pre-treated patients. The mean (standard deviation [SD]) age of patients was 76.9 (8.1) years. A total of 319 (72.8%) were male and 119 (27.2%) were female (Table 1). Cohort 4 was used for the primary analysis and included patients with a minimum follow-up period of 12 months (327 patients in total [93 treatment-naïve patients and 234 pre-treated patients]).
Table 1
Baseline demographics
Treatment-naïve (n = 123)
Pre-treated (n = 315)
All (n = 438)
Age (years)
n = 123
n = 315
n = 438
Mean (SD)
76.2 (8.3)
77.1 (8.0)
76.9 (8.1)
< 80 years
82 (66.7%)
187 (59.4%)
269 (61.4%)
Gender, n (%)
n = 123
n = 315
n = 438
Male
84 (68.3%)
235 (74.6%)
319 (72.8%)
Time between nAMD diagnosis and first brolucizumab injection (months)
n = 121
n = 299
n = 420
Median
0.0
48
36
Quartile 1–quartile 3
0–12
24–84
12–72
Min–max
0–144
0–264
0–264
Missing
2
16
18
The clinical characteristics of the study groups at baseline are outlined in Table 2. Most patients had choroidal neovascularization (CNV) at baseline (83.9% of treatment-naive patients [n = 112] and 70.6% of pre-treated patients [n = 289]). Of the 270 patients with a minimum follow-up period of 12 months, 37 (13.7%) were free of intraretinal fluid (IRF) and subretinal fluid (SRF) at baseline (seven [10.1%] patients in the treatment-naive cohort and 30 [14.9%] patients in the pre-treated cohort). Of note, a total of 91 patients (20.8%) switched to another anti-VEGF during the 12-month follow-up period (14 [11.4%] of treatment-naive patients and 77 [24.4%] of pre-treated patients).
Table 2
Baseline clinical characteristics
Treatment-naïve (n = 123)
Pre-treated (n = 315)
All (n = 438)
nAMD laterality
n= 123
n= 315
n = 438
Proportion with unilateral nAMD
94 (76.4%)
228 (72.4%)
322 (73.5%)
CNV type
n= 93
n= 202
n= 295
Type I
36 (38.7%)
64 (31.7%)
100 (33.9%)
Type II
9 (9.7%)
17 (8.4%)
26 (8.8%)
Type III
5 (5.4%)
3 (1.5%)
8 (2.7%)
PCV (yes)
38 (40.9%)
108 (53.5%)
146 (49.5%)
PCV (no)
0 (0.0%)
1 (0.5%)
1 (0.3%)
PCV (not graded)
5 (5.4%)
9 (4.5%)
14 (4.7%)
Intraretinal fluid (IRF)
n= 87
n= 265
n= 352
Presence
13 (14.9%)
48 (18.1%)
61 (17.3%)
Subretinal fluid (SRF)
n= 105
n= 299
n= 404
Presence
91 (86.7%)
231 (77.3%)
322 (79.7%)
SRF and/or IRF
n= 103
n= 295
n= 398
Presence
92 (89.3%)
251 (85.1%)
343 (86.2%)
Sub-RPE fluid
n= 87
n= 265
n = 352
Presence
42 (48.3)
97 (36.6)
139 (39.5)
CSFT (µm)
n= 49
n= 72
n= 121
Mean (SD)
327 (163)
283 (123)
301 (142)
95% CI
280: 374
255: 312
276: 327
Visual acuity (ETDRS letters)
n= 99
n= 281
n= 380
Mean (SD)
70.3 (16.5)
68.2 (17.3)
68.8 (17.1)
95% CI
67.0: 73.6
66.2: 70.3
67.1: 70.5
Previous anti-VEGF therapy
N/A
n= 315
N/A
Ranibizumab, n (%)
–
26 (8.3)
–
Aflibercept, n (%)
–
243 (77.1)
–
Bevacizumab, n (%)
–
1 (0.3)
–
Ranibizumab + aflibercept, n (%)
–
44 (14.0)
–
Ranibizumab + bevacizumab, n (%)
–
0 (0.0)
–
Aflibercept + bevacizumab, n (%)
–
1 (0.3)
–
Other, n (%)
–
0 (0.0)
–
Values are n (%) unless otherwise stated
Primary Outcome
Absence of SRF and IRF at Baseline and Month 12
Absence of SRF and IRF was evaluated in patients who could be observed at baseline and month 12. In the treatment-naïve cohort, 10.1% (n = 7/69) were free of SRF and IRF at baseline, and this increased to 62.3% (n = 43/69) at month 12. In the pre-treated cohort, 14.9% (n = 30/201) were free of SRF and IRF at baseline, increasing to 43.8% (n = 88/201) at month 12 (Fig. 2).
Fig. 2
Absence of SRF and IRF at baseline date and month 12 by pre-treatment status
In treatment-naïve patients with SRF and/or IRF at baseline, 76.6% (n = 49/64), 65.3% (n = 32/49), and 59.7% (n = 37/62) of patients demonstrated resolution of SRF and IRF at months 3, 6, and 12, respectively (Fig. 3). In pre-treated patients with SRF and/or IRF at baseline, 40.4% (n = 80/198), 41.3% (n = 64/155), and 38.6% (n = 66/171) of patients demonstrated resolution of SRF and IRF at months 3, 6, and 12, respectively (Fig. 3).
Fig. 3
Resolution of both SRF and IRF (among patients with SRF and/or IRF at baseline) at months 3, 6, and 12 in treatment-naïve and pre-treated patients. IRF, intraretinal fluid; SRF, subretinal fluid. McNemar test is used for categorical variables. In cases where the sum of the off-diagonal frequencies is less than 25, the exact p-value is shown. Otherwise, the asymptotic p-value is shown. Absence of each parameter (SRF, IRF) at specified time points compared to baseline. No missing value imputation was performed
Fluid resolution was also assessed for each individual retinal fluid type, i.e. SRF, IRF, and sub-RPE fluid, among patients with presence of that fluid at baseline and those with absence of that fluid at baseline (Fig. 4). Among the treatment-naïve patients with presence of a given retinal fluid type at baseline (i.e. SRF or IRF or sub-RPE fluid), a greater percentage of patients demonstrated fluid resolution at month 12 versus pre-treated patients (SRF: 67.2% vs. 50%; IRF: 75% vs. 37.1%; sub-RPE fluid: 62.9% vs. 34.2%) (Fig. 4). Maintenance of fluid absence (i.e., fluid absence at month 12 in patients without fluid at baseline) ranged from 96.4% to 100% in the treatment-naïve cohort and 82.2–92.4% in pre-treated patients across individual retinal fluid types (Fig. 4).
Fig. 4
Absence of retinal fluid at month 12 by retinal fluid type (i.e. SRF, IRF, sub-RPE fluid). A Percentage of patients without fluid at month 12 among those with fluid at baseline. B Percentage of patients without fluid at month 12 among those without fluid at baseline. SRF, subretinal fluid; IRF, intraretinal fluid; RPE, retinal pigment epithelium
A Kaplan–Meier plot showing time to SRF and IRF resolution among patients with SRF and IRF at baseline is shown in Figure S1. Median time to fluid resolution (months) among those with SRF and IRF at baseline was 1.9 months (95% CI 1.37, 2.23) in the treatment-naive (n = 92) cohort and 3.1 months (95% CI 2.17, 3.77) in the pre-treated cohort (n = 251). Kaplan–Meier plots showing time to SRF resolution (Figure S2), IRF resolution (Figure S3), and sub-RPE fluid resolution (Figure S4), among patients with presence of these respective fluids at baseline, are shown in the supplementary materials.
Visual Acuity
Mean (SD) VA changed by +5.7 (12.5) letters (p < 0.0001) in treatment-naïve patients and −0.5 (10.6) letters in pre-treated patients between baseline date and month 12. Figure 5 shows absolute mean VA values at baseline and month 12 by treatment status.
Fig. 5
Mean visual acuity (VA) at baseline and month 12 in treatment-naïve and pre-treated patients. ETDRS, Early Treatment Diabetic Retinopathy Study; SD, standard deviation; VA, visual acuity. Change in VA over time was determined using a paired t-test analysis. *Statistically significant difference from baseline
Mean (SD) CSFT changed by −105.3 µm (113.2) (p < 0.0001) in treatment-naïve patients and −42.5 µm (83.9) (p < 0.0001) in pre-treated patients between baseline date and month 12. Figure 6 shows the absolute mean CSFT values at baseline and month 12.
Fig. 6
Mean CSFT at baseline and month 12 in treatment-naïve and pre-treated patients. CSFT, central subfield thickness; SD, standard deviation
The median (interquartile range [IQR]) injection interval for pre-treated patients at month 12 was extended by 21 (7.0–35.0) days. Between baseline and month 12, 151 (77.4%) pre-treated patients had a prolonged injection interval of ≥ 1 week, 19 (9.7%) had a stable injection interval, and 25 (12.8%) had a reduced injection interval (≤ 1 week). Mean brolucizumab injection interval distribution for treatment-naïve and pre-treated patients during months 0–12 is shown in Table 3.
Table 3
Mean brolucizumab injection interval distribution for treatment-naïve and pre-treated patients during months 0–12
Treatment-naïve
Pre-treated
All
Mean distribution of injection intervals (weeks) during months 0–12
No. of patients:
93
234
327
< 8 weeks
18 (19.8%)
36 (16.3%)
54 (17.3%)
≥ 8 and < 12 weeks
63 (69.2%)
110 (49.8%)
173 (55.5%)
≥ 12 and < 16 weeks
6 (6.6%)
49 (22.2%)
55 (17.6%)
≥ 16 weeks
4 (4.4%)
26 (11.7%)
30 (9.6%)
Missing
2
13
15
Note: The treatment interval between two brolucizumab doses during maintenance treatment should be no less than 8 weeks
Safety
Overall, 71/438 (16.2%) patients reported a total of 84 AEs, and these are detailed in Table S2. Details of adverse events of special interest (AESI) are presented in Table 4. A total of 41 patients (9.4%) reported 43 AESI (14 treatment-naïve patients [11.4%] reported 15 AESI and 27 pre-treated patients [8.6%] reported 28 AESI). The most frequent AESI was IOI. We report an IOI rate (including the rate of retinal vasculitis/retinal occlusive vasculitis of 0.46% [2/438]) of 8.4% (n = 37/438). The breakdown of IOI events was as follows (Table 4): eye inflammation (14 events in 14 patients [3.2%]; uveitis (10 events in 10 patients [2.3%]; iritis (nine events in nine patients [2.1%]; anterior chamber inflammation (two events in two patients [0.5%]; retinal occlusive vasculitis (one event in one pre-treated patient); retinal vasculitis (one event in one pre-treated patient). Of the 41 patients in whom AESI was reported, 34 (82.9%) of them resolved fully (or resolved with sequelae) by the end of the study (11/14 [78.6%] in treatment-naïve patients and 22/27 [81.5%] in pre-treated patients).
Table 4
Adverse events of special interest
Treatment-naïve (n = 123)
Pre-treated (n = 315)
Patients with any AESI [n (%)]
14 (11.4%)
27 (8.6%)
Male patients with any AESI/male patients (events/patients [%])a
9/84 (10.7%)
18/235 (7.7%)
Female patients with any AESI/female patients (events/patients [%])
5/39 (12.8%)
9/80 (11.3%)
Patients < 80 years with any AESI/patients < 80 years (events/patients [%])
7/82 (8.5%)
18/187 (9.6%)
Patients ≥ 80 years with any AESI/patients ≥ 80 years (events/patients [%])
7/41 (17.1%)
9/128 (7.0%)
IOI events; n (%)
Eye inflammation
9 (7.3%)
5 (1.6%)
Uveitis
1 (0.8%)
9 (2.9%)
Iritis
3 (2.4%)
6 (1.9%)
Anterior chamber inflammation
1 (0.8%)
1 (0.3%)
Retinal occlusive vasculitis
0 (0%)
1 (0.3%)
Retinal vasculitis
0 (0%)
1 (0.3%)
aThere were 319 male and 119 female patients in the overall cohort
Of the 14 AESIs that occurred in the treatment-naïve group, nine (64.3%) occurred ≤ 90 days from the first injection. Of the 27 AESIs that occurred in the pre-treated group, 15 (55.5%) occurred ≤ 90 days from the first injection. The mean (SD) number of brolucizumab injections before an AESI was 2.4 (1.5) injections in the treatment-naïve group and 2.4 (1.8) in the pre-treated group. Mean (SD) VA before AESI onset, during AESI, and after AESI recovery was 66.7 (20.3) letters, 64.1 (17.8) letters, and 71.0 (14.0) letters in the treatment-naïve group, respectively. In the pre-treated group, it was 68.6 (17.2) letters before AESI onset, 58.2 (25.1) letters during AESI, and 63.7 (22.3) after AESI recovery. Four patients in the pre-treated group experienced ≥ 15 letter loss in vision following an AESI. One patient had uveitis (IOI including vasculitis) that completely resolved. One patient had eye inflammation (IOI, including vasculitis) that completely resolved. Two patients had iritis (IOI, including vasculitis) that completely resolved. Details of AESI patients, including best-corrected visual acuity (BCVA) data, injection data, and treatments, are provided in Table S3.
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Discussion
The PHEASANT study is a unique, multicenter, retrospective analysis of Japanese nAMD patients. To the best of our knowledge, this is one of the largest real-world studies to evaluate brolucizumab outcomes in a population of nAMD patients [438 patients], with a minimum 12-month follow-up from eight sites across Japan, resulting in highly representative insight into the real-world outcomes in Japanese nAMD patients (see Table S1).
The primary objective of the PHEASANT study was to evaluate retinal fluid resolution (absence of IRF and absence of SRF) at month 12 after initiation of brolucizumab in real-world Japanese nAMD patients. We report that fluid resolution (SRF and IRF) was better in treatment-naïve patients (SRF and IRF were absent in 59.7% of treatment-naïve patients versus 38.6% in pre-treated patients at month 12). Our findings on fluid resolution are consistent with the pivotal clinical trials HAWK and HARRIER, in which 68.9% (HAWK) and 74.1% (HARRIER) of patients (treatment-naïve) achieved resolution of SRF and IRF at 48 weeks [17]. We also report a similar trend when analyzing the individual retinal fluid types, i.e., SRF (67.2% in treatment-naïve patients versus 50% in pre-treated patients), IRF (75% in treatment-naïve patients versus 37.1% in pre-treated patients), and sub-RPE fluid (62.9% in treatment-naive patients versus 34.2% in pre-treated patients). Overall, our findings align with the growing body of real-world evidence on the use of brolucizumab in clinical practice, which demonstrates fluid resolution after initiation of brolucizumab in both pre-treated patients [18‐20] and treatment-naïve patients [17, 19].
We also report that in patients without retinal fluid at baseline, maintenance of a dry retina (i.e., fluid absence at month 12 in patients without fluid at baseline) was achieved in 96.4–100% of treatment-naïve patients (SRF: 100%; IRF: 96.4%; sub-RPE fluid: 96.4%) and 82.2–92.4% of pre-treated patients (SRF: 82.2%; IRF: 92.4%; sub-RPE fluid: 88.3%). This finding is particularly significant as it has been recently shown that stability of retinal anatomy is an important predictor of visual outcomes in nAMD [21].
Based on Kaplan–Meier analysis, half of the patients with retinal fluid at baseline in the current study achieved dryness within 1.9 months post-brolucizumab initiation. This is consistent with a post hoc analysis of fluid data from HAWK and HARRIER, in which it was reported that 60% of patients achieved sustained dryness with brolucizumab 6 mg at week 8 [17].
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In terms of the impact of brolucizumab treatment on VA, we report that treatment-naïve patients experienced a gain in VA (+5.7 letters) at month 12, while the vision of pre-treated patients remained stable in the same time period. The visual gains observed in the treatment-naïve patients align with findings from another recent study of Japanese nAMD patients. In that study, Matsumoto et al. reported that logMAR BCVA improved from 0.25 ± 0.30 at baseline to 0.10 ± 0.26 (p < 0.01) at week 52 [22]. The VA stability observed in pre-treated patients in the current study was similarly observed in other studies of Japanese nAMD patients who were switched from another anti-VEGF to brolucizumab [23, 24].
Retinal thickness is an important biomarker of disease activity in nAMD, and to date, several studies have demonstrated improvements in CSFT following the switch to brolucizumab in Japanese nAMD patients [23, 24], as well as European [25] and US nAMD populations [10]. The pre-treated patients in the current study experienced similar significant reductions in CSFT following switch to brolucizumab. These findings suggest that brolucizumab may be a useful therapeutic option when nAMD disease control cannot be achieved with other anti-VEGF agents.
We report that in pre-treated patients switched to brolucizumab, the median (IQR) brolucizumab injection interval at month 12 was extended by 21 (7.0–35.0) days. This finding is consistent with those of other retrospective, real-world analyses [10, 26]. In a recent large retrospective study by Coney et al. which looked at injection intervals following a switch to brolucizumab, they reported that injection intervals were extended from baseline to month 12 by 26.9 (19.7, 34.0) days [10]. Similarly, in a retrospective, observational case series conducted in Japan by Ueda-Consolvo et al., treatment intervals were extended by approximately 4 weeks in patients with macular neovascularization following a switch from aflibercept to brolucizumab [26].
Collectively, our findings in relation to retinal fluid resolution, vision, and treatment intervals have important implications for the management of Japanese nAMD patients. Our findings, which align with those of several similar (albeit smaller) studies of Japanese nAMD patients, suggest that brolucizumab may be a useful therapy in the armamentarium of physicians who face an ever-growing nAMD treatment and monitoring burden [27, 28].
We report that the percentage of eyes with an IOI (including eyes with retinal vasculitis/retinal occlusive vasculitis [0.46%]) in the first 12 months was 8.4% (n = 37/438). The higher rate of IOI observed in this cohort, versus the rate of 4.6% in the HAWK and HARRIER studies, aligns with a previously observed higher rate of IOI in Japanese patients. In a post hoc analysis of Japanese patients with polypoidal choroidal vasculopathy (PCV) from the HAWK trial, Ogura et al. reported an IOI rate of 15.4%, but also cautioned that the sample size was relatively small (15.4%, n = 6/39) [29]. Several other studies in Japanese nAMD patients (treatment-naïve and pre-treated patients) also reported higher rates of IOI (11.3–22.1%) than were found in the current study (8.4%) [12, 22, 24, 30].
In treatment-naïve patients who experienced an AESI, mean BCVA after the event was higher than before the AESI. This aligns with findings from a recent study by Hirono et al., who reported that all brolucizumab-treated nAMD patients who experienced an IOI (the rate of IOI in that study was 6.3%) fully recovered with prompt treatment [31]. It should be noted that in the treatment-naïve patients who experienced an AESI, brolucizumab was discontinued after the AESI.
This study has several strengths, including its multicenter approach and a large, real-world sample of naïve and pre-treated patients with a 12-month follow-up. However, certain limitations should be kept in mind when interpreting these results. Firstly, due to the real-world nature of the study, missing data was a key limitation. This was a single-country study, conducted only in Japan, and therefore the results, while accurately reflective of real-world outcomes in Japan, should not be generalized to other countries that may have different practices of ophthalmology in terms of patient monitoring and factors determining time between injections. Due to the real-world nature of the study, and the fact that re-treatment decisions were taken at the discretion of the investigator, it may be prone to bias around re-treatment decisions/injection intervals. To minimize bias, a multicenter design with a relevant sample size was used. Subgroup and sensitivity analyses further increased result robustness and validity. Finally, information on the risk of IOI was available prior to launch in Japan, so it is possible that patients in our study who were selected by their physicians are optimal candidates for brolucizumab, given this information.
Conclusion
In conclusion, our findings show that brolucizumab is an effective treatment in both naïve and refractory Japanese nAMD patients in terms of anatomical and functional parameters, while also reducing the treatment burden on patients and caregivers. The incidence rate of AEs was consistent with the established safety profile of brolucizumab, supporting the overall favorable benefit/risk profile of brolucizumab in this Japanese nAMD population.
Medical Writing, Editorial, and Other Assistance
Medical writing support was provided by Mark Kirby, PhD (Novartis GBS, Ireland) and funded by Novartis Pharma AG, Basel, Switzerland.
Author Contributions
Concept and study design: Masayuki Ohnaka; Tina Maio-Twofoot; Helene Karcher. Analysis and interpretation: Masayuki Ohnaka; Yoichi Sakurada; Atsushi Hayashi; Kazuaki Kadonosono; Hitoshi Ohno; Ryusaburo Mori; Hidetaka Matsumoto; Ippei Nagamori; Yuki Murata; Tina Maio-Twofoot; Helene Karcher; Hidenori Takahashi. Data collection: Masayuki Ohnaka; Yoichi Sakurada; Atsushi Hayashi; Kazuaki Kadonosono; Hitoshi Ohno; Ryusaburo Mori; Hidetaka Matsumoto; Ippei Nagamori; Yuki Murata; Hidenori Takahashi. Obtained funding: Tina Maio-Twofoot; Helene Karcher. Overall responsibilities: Masayuki Ohnaka; Tina Maio-Twofoot.
Funding
This study was funded by Novartis Pharma AG, Basel, Switzerland. Novartis Pharma AG funded the journal’s Rapid Service fee and the medical writing support.
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
Masayuki Ohnaka: Speaker (Bayer, Chugai, Novartis, Santen and Senju); Yoichi Sakurada: None; Atsushi Hayashi: Research (Nitto medic, Senju, Bayer, Kowa, Chugai, Alcon, R. E. medical, AMO Japan, AbbVie, Mitsubishi Tanabe Pharma, Santen, Siemens, Tsumura, and Ellex), Funding (AMO Japan, Alcon, Hoya, and Santen). Kazuaki Kadonosono: Funding (Alcon, Chugai, Hoffman-La Roche, Hoya, Kowa, Kyowa medical, R.E. Medical Santen, Senju); Hitoshi Ohno: Funding (Allergan Japan, Senju, Novartis, Bayer for clinical trial); Ryusaburo Mori: Speaker (Bayer, Senju, Chugai, Santen, Novartis, Boehringer Ingelheim, Kyowa Kirin); Hidetaka Matsumoto: Speaker (Novartis, Chugai, Bayer, Santen, and Senju), Research (Novartis and Bayer); Ippei Nagamori: Novartis employee; Yuki Murata: Novartis employee; Tina Maio-Twofoot: Novartis employee; Helene Karcher: Philip Morris Products S.A., Neuchatel, Switzerland. Ex-Novartis employee and shareholder; Hidenori Takahashi: Funding (Kyowa Kirin, Novartis, Bayer, and Linical), Personal interest (DeepEyeVision), Consultant (Boehringer Ingelheim), Consultant and speaker (Santen, Bayer, Senju, Boehringer Ingelheim, MSD, Chugai, Hoya, Novartis, Nikon TBC).
Ethical Approval
This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. The study was approved by an ethics committee at each study center (Kansai Medical University Hospital: 2021267; Toyama University: R2021136; University of Yamanashi Hospital: 2553; Yokohama City University: F220600027; Jichi Medical University: 22-034; Chofu Eye Clinic: LIN08548; Nihon University Hospital: 20220109; Gumna University Hospital: IRB2021-055(1946)). Patient consent: All subjects provided informed consent to participate in the study.
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Je höher der BMI, umso höher ist das Risiko, bei einer Infektion zu sterben. Das gilt nicht nur für Covid-19, sondern für Infektionen allgemein. Bei einer Grad-III-Adipositas ist die Mortalität während einer Infektion sogar verdreifacht. Darauf deuten Daten aus Finnland und Großbritannien.
Periphere Fazialisparesen sollten nicht vorschnell als idiopathisch klassifiziert werden. Vor allem bei atypischen Manifestationen gilt es, auf dem Quivive zu sein. Der Fall einer 73-Jährigen zeigt, warum.
Bei der Festlegung der Intervalle für Kontrollkoloskopien nach einer Polypektomie sollten nicht ausschließlich polypenbezogene Merkmale berücksichtigt werden. Wie eine internationale Studie zeigt, beeinflussen auch individuelle demografische Faktoren, wie Geschlecht, Body-Mass-Index und Ethnie, das Rezidivrisiko.
In einer Kohortenstudie wurde ein Zusammenhang zwischen oralen Bakterien und Pilzen und dem Auftreten von Pankreaskarzinomen gesehen. Diese Assoziation könnte helfen, Patientinnen und Patienten für gezielte Vorsorgeuntersuchungen ausfindig zu machen.
