Early Experience With Brolucizumab Treatment of Neovascular Age-Related Macular Degeneration

Ana Bety Enríquez; Caroline R Baumal; Ashley M Crane; Andre J Witkin; David R Lally; Michelle C Liang; José Ramón Enríquez; David A Eichenbaum

doi:10.1001/jamaophthalmol.2020.7085

. 2021 Feb 25;139(4):1–8. doi: 10.1001/jamaophthalmol.2020.7085

Early Experience With Brolucizumab Treatment of Neovascular Age-Related Macular Degeneration

Ana Bety Enríquez ¹, Caroline R Baumal ^1,^✉, Ashley M Crane ², Andre J Witkin ¹, David R Lally ^3,⁴, Michelle C Liang ¹, José Ramón Enríquez ⁵, David A Eichenbaum ²

¹New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts

²Retina-Vitreous Associates of Florida, Tampa

³New England Retina Consultants, Springfield, Massachusetts

⁴Department of Surgery, University of Massachusetts Medical School–Baystate, Springfield

⁵Harvard University, Cambridge, Massachusetts

Accepted for Publication: December 29, 2020.

Published Online: February 25, 2021. doi:10.1001/jamaophthalmol.2020.7085

Correction: This article was corrected on April 21, 2021, to fix typographical errors in the Results and update the Supplement.

^✉

Corresponding Author: Caroline R. Baumal, MD, New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine, 800 Washington St, Box 450, Boston, MA 02116 (cbaumal@tuftsmedicalcenter.org).

Author Contributions: Drs A. Enríquez and Baumal had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs A. Enríquez and Baumal are co–first authors of this manuscript.

Concept and design: A. Enríquez, Baumal, Eichenbaum.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: A. Enríquez, Baumal, Witkin, J. Enríquez, Eichenbaum.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: A. Enríquez, Baumal, J. Enríquez.

Administrative, technical, or material support: Baumal, Crane, Witkin, Liang.

Supervision: Baumal, Witkin, Lally, Liang, Eichenbaum.

Conflict of Interest Disclosures: Dr Baumal reported receiving personal fees from Genentech, Novartis, and Zeiss outside the submitted work. Dr Crane reported serving as an investigator for Genentech, Regeneron, Allergan, Novartis, Ophthotech, Ophthea, Mylan, Chengdu, Gyroscope, Alkahest, Kodiak, Santen, and Bayer outside the submitted work. Dr Witkin reported receiving personal fees from Allergan outside the submitted work. Dr Lally reported receiving grants and personal fees from Novartis outside the submitted work. Dr Liang reported receiving personal fees from Allergan outside the submitted work. Dr Eichenbaum reported receiving grants and personal fees from Novartis, Genentech, Regeneron, Allergan, Clearside, Alimera, EyePoint, Gyroscope, and Kodiak; grants from Ophthotech, Ophthea, Mylan, Chengdu, NGM, Alkahest, and Iveric Bio; personal fees from Notal Vision, RecensMedical, and Dutch Ophthalmic outside the submitted work; and having equity in Hemera Biosciences, Boston Image Research Center, US Retina, and Network Eye. No other disclosures were reported.

^✉

Corresponding author.

PMCID: PMC7907988 PMID: 33630045

Key Points

Question

What are the early outcomes associated with brolucizumab injection for neovascular age-related macular degeneration (nAMD)?

Findings

In this case series of 172 eyes evaluated after brolucizumab treatment of nAMD, mean visual acuity (VA) remained unchanged and mean central subfield thickness (CST) decreased. Intraocular inflammation (IOI) observed in 8.1% of eyes was usually mild, often resolving without treatment; potential IOI risk factors included female sex and bilateral same-day brolucizumab treatment.

Meaning

These findings suggest that brolucizumab treatment may be associated with stable VA and reduction in CST in patients with nAMD; further exploration of IOI is warranted to understand its pathogenesis, risk factors, and management.

Abstract

Importance

Outcome data are limited regarding early experience with brolucizumab, the most recently approved anti–vascular endothelial growth factor (VEGF) agent for the treatment of neovascular age-related macular degeneration (nAMD).

Objective

To report clinical outcomes after intravitreous injection (IVI) of brolucizumab, 6 mg, for nAMD.

Design, Setting, and Participants

This retrospective case series conducted at 15 private or academic ophthalmological centers in the United States included all consecutive patients with eyes treated with brolucizumab by 6 retina specialists between October 17, 2019, and April 1, 2020.

Exposures

Treatment with brolucizumab IVI, 6 mg.

Main Outcomes and Measures

Change in mean visual acuity (VA) and optical coherence tomography parameters, including mean central subfield thickness and presence or absence of subretinal and/or intraretinal fluid. Secondary outcomes included ocular and systemic safety.

Results

A total of 172 eyes from 152 patients (87 women [57.2%]; mean [SD] age, 80.0 [8.0] years) were included. Most eyes (166 [96.5%]) were not treatment naive, and 65.7% of these eyes (109 of 166) were switched from the prior anti-VEGF agent because of persistent fluid detected on optical coherence tomography scans. Study eyes received a mean (SD) of 1.46 (0.62) brolucizumab IVIs. The mean (SD) VA prior to starting brolucizumab was a 64.1 (15.9) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (Snellen equivalent, 20/50) and was a 63.3 (17.2) ETDRS letter score (Snellen equivalent, 20/63) at the last study evaluation (mean difference, 0.8; 95% CI, −2.7 to 4.3; P = .65). When analyzed by number of brolucizumab IVIs, the presence or absence of fluid prior to starting brolucizumab, or the presence or absence of intraocular inflammation after receiving brolucizumab, there was no difference in mean VA prior to starting brolucizumab compared with after brolucizumab IVIs or at the final study evaluation. The mean (SD) central subfield thickness in all eyes prior to starting brolucizumab was 296.7 (88.0) μm and was 269.8 (66.5) μm at the last study examination (mean difference, 26.9 µm; 95% CI, 9.0-44.7 µm; P = .003). Intraocular inflammation was reported in 14 eyes (8.1%) and was self-limited and resolved without treatment in almost half those eyes (n = 6). One previously reported eye (0.6%) had occlusive retinal vasculitis and severe loss of vision.

Conclusions and Relevance

In this analysis of brolucizumab IVI for nAMD, VA remained stable, with a reduction in central subfield thickness. Intraocular inflammation events ranged from mild with spontaneous resolution to severe occlusive retinal vasculitis in 1 eye.

This case series reports clinical outcomes after intravitreous injection of brolucizumab, 6 mg, for neovascular age-related macular degeneration.

Introduction

Brolucizumab, 6 mg (Novartis International AG), was approved for treatment of neovascular age-related macular degeneration (nAMD) by the US Food and Drug Administration on October 8, 2019, followed by approval by the European Medicines Agency in February 2020.^1,2,3,4 It is a humanized single-chain variable antibody fragment that binds to all human isoforms of anti–vascular endothelial growth factor (VEGF) A.^{5,6,7,8,9,10,11} Its pharmacologic properties include molecular stability, high solubility, and a small molecular size of 26 kDa, allowing it to achieve 10 times higher molar concentrations compared with aflibercept.^7,8,9,12 These characteristics are believed to account for the greater reduction in the central subfield thickness (CST) on optical coherence tomography (OCT) scans and for its potentially longer durability observed in the pivotal phase 3 clinical HAWK and HARRIER trials.^{7,8,9,12,13,14} These trials met their primary end points at 48 weeks, demonstrating noninferiority of visual results in treatment-naive eyes with nAMD receiving brolucizumab, 6 mg or 3 mg, compared with aflibercept, 2 mg.¹³ Secondary outcomes favoring brolucizumab were greater CST reductions and extended dosing intervals to 12 weeks in more than half of eyes treated with 6 mg of brolucizumab (after 3 monthly loading doses).¹³

The safety profile of brolucizumab intravitreous injection (IVI) was similar to that of aflibercept in the initial HAWK and HARRIER trials, with the exception of a higher rate of inflammatory events (4.4%) in eyes treated with 6 mg of brolucizumab compared with aflibercept (0.8%).¹³ This finding was offset by the lack of a significant difference in rates of severe vision loss at weeks 48 and 96 between eyes treated with brolucizumab and those treated with aflibercept.^15,16 Subsequent to brolucizumab’s approval in the United States, cases of intraocular inflammation (IOI) and retinal vasculitis associated with its use were reported, leading to notifications from the American Society of Retina Specialists Research and Safety in Therapeutics Committee and Novartis.^{17,18,19,20,21,22,23,24,25} A safety review committee convened by Novartis to independently review IOI events from the HAWK and HARRIER studies reported IOI events in 4.6% (50 of 1088) of eyes treated with brolucizumab (3-mg and 6-mg groups combined), of which 3.3% (36 of 1088) of eyes had concomitant retinal vasculitis and 2.1% (23 of 1088) of eyes had retinal vasculitis with retinal vascular occlusion.²² Overall, the risk of developing IOI of any severity and losing 15 or more letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) score was 0.7% (8 of 1088). The present study was undertaken to evaluate the experience of 6 retina specialists (C.R.B., A.M.C., A.J.W., D.R.L., M.C.L., and D.A.E) who were early adopters of brolucizumab, focusing on visual and anatomical outcomes and the safety profile of brolucizumab for treating nAMD.

Methods

Population

All consecutive patients with nAMD treated with brolucizumab IVI, 6 mg, between October 17, 2019, and April 1, 2020, by 6 retina specialists at 15 locations were identified using electronic medical records or injection logbooks. Study inclusion required nAMD as the primary indication for treatment. A complete baseline clinical examination with both a visual acuity (VA) assessment and OCT with at least 1 follow-up visit after brolucizumab IVI was required. Four retina specialists (A.B.E., C.R.B., A.M.C., and D.R.L.) performed a detailed medical record review to evaluate deidentified data and OCT images. Institutional review board approval was obtained for retrospective review from Tufts Medical Center, which waived informed consent in accordance with 45CFR46.104(d). Data were deidentified and protected by privacy safeguards. This study followed the rules of the Health Insurance Portability and Accountability Act and adhered to the tenets of the Declaration of Helsinki.²⁶

Statistical Analysis

Statistical tests were performed using IBM SPSS software, version 25 (SPSS Inc), Stata/SE software, version 16.1 (StataCorp LLC), and RStudio software, version 1.3.1073 (PBC). Visual acuity was converted to an ETDRS letter score for analysis.^{27,28,29,30,31,32,33,34,35,36} Because ETDRS acuity includes protocol refraction, this conversion can only be approximate. Data were analyzed with frequency and descriptive statistics. Quantitative variables with a parametric distribution were reported as mean (SD) values, while nonparametric variables were reported as median values and interquartile ranges (IQRs) or ranges. Qualitative variables were reported as absolute frequencies and percentages. Differences in the mean values were assessed using 2-sided t tests with a 95% CI. Correction for multiple analysis was performed using the Bonferroni and false discovery rate methods. Relative risks were calculated with 95% CIs. Correlation evaluations were performed with nonparametric statistical analysis. P < .05 was considered significant.

Results

Baseline Demographic Characteristics

Over the 24-week period, 172 consecutive eyes from 152 patients with nAMD received brolucizumab IVI. Eighty-seven patients (57.2%) were female, the mean (SD) age was 80.0 (8.0) years, and 148 (97.4%) were White (eTable 1 in the Supplement).

Features of nAMD Prior to Brolucizumab Use

Only 4 of 172 eyes (2.3%) were treatment naive prior to starting treatment with brolucizumab IVI. Details of prior anti-VEGF agents were unavailable for 2 eyes (1.2%). The remaining 166 non–treatment-naive eyes (96.5%) had a median of 18 prior anti-VEGF IVIs (IQR, 9-32 IVIs) during a median of 29.5 months (IQR, 12-48 months). Prior to commencing brolucizumab treatment, 7 eyes (4.1%) had a documented previous ocular inflammatory event (eTable 1 and eTable 2 in the Supplement).

Brolucizumab IVI

A total of 105 eyes (61.0%) received a single brolucizumab IVI, 55 eyes (32.0%) received 2 brolucizumab IVIs, and 12 eyes (7.0%) received 3 brolucizumab IVIs. A mean (SD) of 1.46 (0.62) brolucizumab IVIs (median, 1 IVI; range, 1-3 IVIs) were given. The clinical and OCT findings prior to and after each brolucizumab IVI are summarized in eTable 3 in the Supplement. Simultaneous with the first, second, and third brolucizumab IVI, there were 56, 16, and 4 contralateral eyes, respectively, that also received an anti-VEGF IVI on the same day as brolucizumab.

Visual Acuity

The mean (SD) VA (172 eyes) before the first brolucizumab IVI was 64.1 (15.9) ETDRS letter score (Snellen equivalent, 20/50). The mean (SD) VA after the first brolucizumab IVI (172 eyes) was a 63.3 (17.2) ETDRS letter score (mean difference from prior to brolucizumab, 0.8; 95% CI, −2.7 to 4.3; P = .65) (Snellen equivalent, 20/63); after the second brolucizumab IVI (67 eyes), it was a 66.0 (15.2) ETDRS letter score (mean difference from prior to brolucizumab, –1.9; 95% CI, −6.4 to 2.5; P = .39) (Snellen equivalent, 20/50); after the third brolucizumab IVI (12 eyes), it was a 68.1 (10.5) ETDRS letter score (mean difference from prior to brolucizumab, –4.0; 95% CI, −13.1 to 5.1; P = .39) (Snellen equivalent, 20/50); and at the final examination (172 eyes), it was a 63.3 (17.2) ETDRS letter score (mean difference from prior to brolucizumab, 0.8; 95% CI, −2.7 to 4.3; P = .65) (Snellen equivalent, 20/63) (eFigure 1 in the Supplement). No change in mean VA was detected at the follow-up visits, regardless of whether the patient received 1, 2, or 3 brolucizumab IVIs (Figure 1).

Figure 1. — Vertical lines indicate 95% CIs. ETDRS indicates Early Treatment Diabetic Retinopathy Study.

OCT Findings

Figure 2 shows CST findings stratified by number of brolucizumab IVIs received. The mean (SD) CST before starting brolucizumab (151 eyes) was 296.7 (88.0) μm; after 1 brolucizumab IVI (158 eyes), it was 269.7 (66.1) μm (mean difference from prior to brolucizumab, 27.0 µm; 95% CI, 9.6-44.3 µm; P = .002); after 2 brolucizumab IVIs (57 eyes), it was 275.4 (63.9) μm (mean difference from prior to brolucizumab, 21.3 µm; 95% CI, −3.7 to 46.3 µm; P = .10); and after 3 brolucizumab IVIs (6 eyes), it was 297.0 (63.0) μm (mean difference from prior to brolucizumab, −0.3 µm; 95% CI, −71.5 to 70.9 µm; P = .99) (eFigure 2 in the Supplement). The mean (SD) CST at the last study evaluation (144 eyes) was 269.8 (66.5) μm (mean difference from prior to brolucizumab, 26.9 µm; 95% CI, 9.0-44.7 µm; P = .003).

Prior to receiving any brolucizumab, 113 eyes (65.7%) had fluid detected on OCT scans (77 eyes with subretinal fluid, 19 with intraretinal fluid, and 17 with subretinal fluid and intraretinal fluid). Fifty eyes (44.2% of eyes with fluid) had complete resolution of fluid detected on OCT scans after 1 brolucizumab IVI, and an additional 6 eyes (5.3% of eyes with fluid) had resolution of fluid with 2 brolucizumab IVIs. Fifty-seven eyes (50.4% of eyes with fluid) did not show resolution of fluid at the last examination after a mean (SD) of 1.58 (0.68) brolucizumab IVIs (median, 1 IVI; range, 1-3 IVIs). The mean VA was unchanged prior to the first brolucizumab IVI (0.6 ETDRS letter score; 95% CI, −4.1 to 5.3; P = .80) and at the last study follow-up evaluation (mean difference from prior to brolucizumab, 0.7 ETDRS letter score; 95% CI −4.0 to 5.4; P = .77) when eyes were stratified based on the presence of fluid detected on OCT scans prior to starting brolucizumab treatment (eFigure 3 in the Supplement). The mean (SD) CST was 314.3 (94.6) μm prior to starting brolucizumab treatment and decreased to 272.0 (72.2) μm after the first brolucizumab IVI (mean difference from prior to brolucizumab, 42.3 µm; 95% CI, 19.7-64.9 µm; P < .001); this reduction was maintained throughout the study, showing a mean (SD) CST of 273.3 (74.0) μm at the last study evaluation (mean difference from prior to brolucizumab, 41.1 µm; 95% CI, 17.3-64.8 µm; P = .001) (eFigure 4 in the Supplement).

Follow-up

The median time between the last brolucizumab IVI and final study evaluation was 42.5 days (IQR, 33-56 days). Additional follow-up was limited owing to coronavirus disease 2019 (COVID-19) pandemic restrictions. In 65 eyes (37.8%), brolucizumab treatment was stopped by the physician and switched to another anti-VEGF therapy (eTable 3 in the Supplement).

Adverse Events

Ocular Adverse Events

None of the 4 treatment-naive eyes developed an ocular adverse event after treatment with brolucizumab. Ocular adverse events included IOI associated with brolucizumab treatment (14 eyes [8.1%]), endophthalmitis (1 eye [0.6%]), IOI with uncertain association with brolucizumab treatment (1 eye [0.6%]), vitreous opacity without IOI (1 eye [0.6%]), intraocular pressure elevation (1 eye [0.6%]), and posterior vitreous detachment (1 eye [0.6%]) (eTable 4 in the Supplement). The endophthalmitis was presumably of bacterial origin, based on its adequate response to intravitreous antibiotic treatment (vancomycin), because a culture was not taken. Intraocular inflammation with uncertain association with brolucizumab treatment pertains to 1 eye with a history of IOI after aflibercept IVI that received 2 brolucizumab IVIs followed by ranibizumab. Seventy-seven days after the second brolucizumab IVI and 35 days after the ranibizumab IVI, the patient developed IOI that completely resolved with difluprednate eye drops.

Intraocular Inflammation

Fourteen eyes (8.1%) from 13 patients (8 women) developed IOI associated with brolucizumab treatment. There was no history of inflammation associated with another anti-VEGF agent in these eyes. Female sex showed a relative risk of 1.27 for IOI (95% CI, 0.44-3.61). The previous number of anti-VEGF IVIs (median, 18 IVIs; IQR, 11.5-26.0 IVIs) did not show a correlation with development of IOI (Spearman ρ = 0.011; P = .89).

The median time from brolucizumab IVI to documentation of IOI was 48.5 days (IQR, 41.3-59.8 days). Intraocular inflammation presented with vitreous cells only (9 of 14 eyes [64.3%]), anterior segment cells only (2 of 14 eyes [14.3%]), both vitreous and anterior segment cells (2 of 14 eyes [14.3%]), or combined anterior and vitreous cells with occlusive retinal vasculitis (1 of 14 eyes [7.1%]).¹⁷ The single eye with IOI and occlusive retinal vasculitis was previously reported in the series from Baumal and associates¹⁷ and was included in this case series because it was found to meet the inclusion criteria. Severity of IOI was mild in 10 of 14 eyes (71.4% of eyes with IOI), moderate in 3 of 14 eyes (21.4% of eyes with IOI), and severe in 1 of 14 eyes (7.1% of eyes with IOI).^37,38 One eye developed localized vitreous opacities of medium internal reflectivity in the quadrant where brolucizumab was injected after oral and topical corticosteroid treatment of vitreous cells (Figure 3).

Figure 3. — A man in his 80s presented with floaters and blurred vision in his right eye 48 days after his first and only brolucizumab IVI. He was switched to brolucizumab owing to persistent subretinal fluid. Clinical examination revealed IOI with anterior segment and vitreous cells. Near-infrared reflectance image (A) and cross-sectional macular optical coherence tomography (OCT) scan (B) with enhanced vitreous imaging (Heidelberg Spectralis; Heidelberg Engineering) revealed hyperreflective vitreous opacities, compatible with vitreous cells and condensations (white arrowheads). He was treated with topical and oral corticosteroids and the IOI resolved. Subsequently, he developed small granular vitreous opacities in the region of the injection. Color fundus photograph 8 weeks after brolucizumab IVI (C) showed yellow opacities, and an ocular ultrasonogram (D) confirmed the presence of hyperechoic opacities (white arrowheads) of medium internal reflectivity.

No change in the mean VA was found when eyes were stratified based on the presence or absence of IOI (eFigure 5 in the Supplement). When analyzed by the change in number of ETDRS letters at the final study evaluation, 11 eyes (78.6% of 14 eyes with IOI) had a VA change of ±4 ETDRS letters, and 3 eyes (21.4% of 14 eyes with IOI) had a gain of 5 or more ETDRS letters. Seven of 14 eyes (50.0% of eyes with IOI) lost 5 or more ETDRS letters; 2 of these eyes lost 15 or more ETDRS letters. The mean CST in eyes with IOI was lower than in eyes that did not develop IOI after receiving 1 brolucizumab IVI (44.8 µm; 95% CI, 7.8-81.8 µm; P = .02) and at the last study evaluation (47.9 µm; 95% CI, 9.2-86.5 µm; P = .02) (Figure 4). However, development of IOI did not correlate to CST before starting brolucizumab treatment (Spearman ρ = –0.161; P = .048).

Figure 4. — Vertical lines indicate 95% CIs. IVI indicates intravitreous injection.

^aOnly 1 eye in this group received a third brolucizumab IVI with follow-up, accounting for the lack of 95% CI.

Three of the 14 eyes with IOI had received bilateral same-day brolucizumab IVI and developed uniocular IOI. Also, 1 patient had received bilateral brolucizumab IVI and developed mild bilateral vitreous cells. These 5 eyes with IOI received a median of 13 prior anti-VEGF IVIs (IQR, 9.5-19.0 IVIs) and had no history of IOI, and the patients received a diagnosis of IOI at the clinical examination that followed the bilateral brolucizumab IVI. The administration of bilateral same-day brolucizumab IVI showed a relative risk of 1.72 (95% CI, 0.61-4.85) for IOI development.

Management of IOI was determined by the physician. Three of 14 eyes (21.4%) with mild IOI, consisting of vitreous cells only, were observed with spontaneous resolution. Another 3 of 14 eyes (21.4%) with mild vitreous cells were not prescribed anti-inflammatory treatment and received an anti-VEGF IVI on the same visit in which vitreous cells were diagnosed (ranibizumab in 2 eyes and aflibercept in 1 eye); the IOI in these 3 eyes resolved spontaneously without sequelae. One eye with mild vitreous cells had resolution of the IOI event after a single drop of loteprednol etabonate that was placed while in the office (because the patient was nonadherent with eye drops). Treatment in the remaining 7 eyes (50.0% of 14 eyes with IOI) included corticosteroid eye drops (4 eyes), topical and oral corticosteroid (1 eye), topical corticosteroid with subtenon triamcinolone acetonide (1 eye), and topical, subtenon, and oral corticosteroid combined with vitrectomy and intraoperative triamcinolone (1 eye).¹⁷ After the IOI event, 11 eyes switched to a different anti-VEGF (ranibizumab [n = 2], aflibercept [n = 8], and unspecified anti-VEGF agent [n = 1]).

Discussion

Our multicenter study was initially conceived when brolucizumab was approved, with the goal of determining its performance in a clinical practice setting (so-called real-world setting) focusing on vision and OCT. The initial study design called for assessments after the 3 monthly loading doses. However, owing to early reports of IOI associated with occlusive retinal vasculitis after brolucizumab treatment,^17,18,19,25 followed by the COVID-19 pandemic imposing limitations on patient visits, the use of this agent by retina specialists changed such that 3 monthly loading doses were not necessarily the standard regimen. Therefore, this study was modified to evaluate the data that were available from a consecutive series of eyes with nAMD treated with brolucizumab.

In the present analysis, the mean VA did not change after 1, 2, or 3 brolucizumab IVIs or at the final follow-up visit (Figure 1). Furthermore, the mean VA did not change regardless of the baseline fluid status (eFigure 3 in the Supplement) or the presence or absence of IOI (eFigure 5 in the Supplement). Several factors should be considered when interpreting VA findings. Study eyes received a mean of only 1.46 brolucizumab IVIs, which may be too limited a number of injections to evaluate its association with VA. Most study eyes (96.5%) were not treatment naive and thus already had varying degrees of VEGF inhibition, which precludes direct comparison with VA findings from treatment-naive eyes in the HAWK and HARRIER trials.¹³ Also, most physicians reported that the anti-VEGF switch was undertaken owing to persistent fluid or to extend the interval between IVIs, rather than to improve VA. Finally, many of these eyes previously treated with anti-VEGF agents had fluid detected on OCT scans prior to starting brolucizumab treatment, which may have been chronic or recurrent and could have affected the outer retina anatomy and thus limited visual improvement.

With respect to OCT, 49.6% of eyes that had fluid detected on OCT scans prior to starting brolucizumab treatment showed fluid resolution at the final study evaluation. When specifically evaluating the non–treatment-naive eyes with preexisting fluid, the fluid resolved after the first brolucizumab IVI in 43.1% of these eyes. Also, a reduction in CST in all eyes with fluid prior to starting brolucizumab treatment was noted after the first brolucizumab IVI; this association appeared to be maintained until the last study evaluation. These findings are consistent with those of the HAWK and HARRIER studies, in which brolucizumab treatment demonstrated superior effectiveness in resolving fluid detected on OCT scans, notably in the first 16-week matched phase of the trials.¹³ Our study demonstrated a reduction in CST after brolucizumab treatment in previously treated eyes with nAMD with persistent fluid prior to switching therapy, suggesting potential effectiveness in this specific population. Similar findings were noted in the BREW (Brolucizumab—Early Real-World Experience) study retrospectively evaluating 42 eyes after brolucizumab treatment.³⁹ Data on non–treatment-naive eyes with nAMD from the ongoing MERLIN trial (ClinicalTrials.gov identifier NCT03710564) should clarify these findings.

Intraocular inflammation has been described after IVI with other anti-VEGFs at an estimated rate of between 0.3% and 2.9% per injection, and IOI was noted in 4.4% of eyes treated with brolucizumab in the HAWK and HARRIER studies.^{22,40,41,42,43,44,45} Clinician knowledge about the incidence of IOI from the phase 3 studies and reports of occlusive vasculitis may play a role in the higher rate of IOI after brolucizumab treatment in our study (8.1%).¹³ There was only 1 case of IOI associated with occlusive retinal vasculitis,¹⁷ for a rate of 0.6% in our series, compared with 2.1% of eyes observed by the safety review committee post hoc review of the HAWK and HARRIER studies.²² Although our series had limited patient follow-up, the risk of developing IOI of any severity and losing 15 or more letters was 1.2% (2 of 172) compared with 0.7% (8 of 1088) from the safety review committee post hoc review of the HAWK and HARRIER studies.²²

Risk factors identified in our series that may play a role in development of IOI include female sex and bilateral same-day brolucizumab treatment. Female sex was noted in other series as a risk factor for IOI with occlusive retinal vasculitis.^17,24,25 One hypothesis for development of IOI is an immune response to the drug, which is supported by delayed onset of IOI, the high prevalence of preexisting antibrolucizumab antibodies (36%-52%), the high prevalence of induced or boosted levels of antibrolucizumab antibodies (23%-25%) after initiation of brolucizumab, and the fact that the incidence of IOI was higher among patients with induced or boosted antidrug antibodies (6%) compared with those without treatment-emergent antidrug antibodies (2%).²⁵ If such an immune response is involved in the pathogenesis of IOI, bilateral injections may increase exposure to a causative antigen. Although eyes that developed IOI had a lower mean CST after the first brolucizumab IVI and at the last study evaluation compared with eyes that did not develop IOI, the Spearman rank test did not confirm the correlation between CST prior to starting brolucizumab and IOI. The number of prior anti-VEGF IVIs was not correlated with the development of IOI.

There is limited information regarding the optimal treatment of the spectrum of IOI events. In the present series, most IOI events (71.4% [10 of 14]) were mild. Corticosteroid eye drops were noted by treating physicians to resolve anterior and vitreous inflammation; however, some eyes with mild IOI improved without therapy. Baumal and colleagues¹⁷ noted that 1 case of IOI progressed to occlusive retinal vasculitis despite corticosteroid treatment, while 2 cases of occlusive vasculitis resolved after intravitreous and/or oral corticosteroids. Based on these findings, we recommend corticosteroids for IOI vs observation after excluding an infectious cause; however, this treatment may be modified when the pathogenesis is better understood.

Limitations

This case series has some limitations, including its retrospective nature (ie, the results depend on the reporting characteristics and treatment preferences of the retina specialists). A heterogeneous group of patients with prior treatment of nAMD was included, and the lack of a control group precludes direct comparison with pivotal studies. The COVID-19 pandemic affected the ability of study patients to return for prolonged follow-up examinations.

Conclusions

From this large retrospective series composed primarily of non–treatment-naive eyes, the mean VA was stable and the mean CST was reduced at the last study evaluation. Intraocular inflammation was noted in 8.1% of eyes, was usually mild, and resolved in almost half of eyes without treatment. There was no difference in the mean VA at the last examination in eyes that developed IOI. Exploratory risk factors for IOI include bilateral same-day brolucizumab and female sex.

Supplement.

eTable 1. Patient Characteristics (Medical and Ocular History) Prior to Starting Brolucizumab

eTable 2. Treatment for Neovascular Age-Related Macular Degeneration (nAMD) Prior to Starting Brolucizumab

eTable 3. Clinical and Optical Coherence Tomography (OCT) Findings Prior to and After Brolucizumab Treatment

eTable 4. Events (Ocular and Systemic) Reported in Eyes After Brolucizumab Treatment

eFigure 1. Visual Acuity (VA) Before and After Brolucizumab Injection in All Eyes

eFigure 2. Central Subfield Thickness (CST) Before and After Brolucizumab Injection in All Eyes

eFigure 3. Visual Acuity (VA) Stratified by Presence or Absence of Fluid Prior to Brolucizumab Injection

eFigure 4. Central Subfield Thickness (CST) Stratified by Presence or Absence of Fluid Prior to Brolucizumab Injection

eFigure 5. Visual Acuity (VA) Stratified by Presence or Absence of an Intraocular Inflammation (IOI) Event

Click here for additional data file.^{(351.5KB, pdf)}

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