Somnath Chakraborty,Jay Umed Sheth
Response of extra-large pigment epithelial detachment to intravitreal brolucizumab injection
Brolucizumab,Macular neovascularization,Pigment epithelial detachment,Anti-vascular endothelial growth factor
Purpose To determine the role of intravitreal injection (IVI) of brolucizumab for extra-large pigment epithelial detachment (PED) secondary to macular neovascularization (MNV). Observations A prospective, non-randomized, uncontrolled case series of three eyes of three patients with extra-large PED (maximum height >350 μm) due to untreated MNV was undertaken at a single center. All three eyes showed significant improvement in the PED height by week 4, with complete resolution by week 8 in two of the three. The third patient who received the second dose is scheduled for a follow-up. Simultaneous notable visual improvement was also observed in all of the eyes. Furthermore, there were no ocular or systemic safety concerns in any of the cases. Conclusions and Importance Our real-world case series indicates that intravitreal brolucizumab is efficacious and safe for the management of extra-large PEDs in treatment-naïve MNV eyes. To better understand brolucizumab's mechanism of action, particularly at the sub-RPE and choroidal levels, and the underlying functional principle for the PED response, more study of the drug's pharmacotherapeutics is warranted.
Response of extra-large pigment epithelial detachment to intravitreal brolucizumab injection

To determine the role of intravitreal injection (IVI) of brolucizumab for extra-large pigment epithelial detachment (PED) secondary to macular neovascularization (MNV).

A prospective, non-randomized, uncontrolled case series of three eyes of three patients with extra-large PED (maximum height >350 μm) due to untreated MNV was undertaken at a single center. All three eyes showed significant improvement in the PED height by week 4, with complete resolution by week 8 in two of the three. The third patient who received the second dose is scheduled for a follow-up. Simultaneous notable visual improvement was also observed in all of the eyes. Furthermore, there were no ocular or systemic safety concerns in any of the cases.

Our real-world case series indicates that intravitreal brolucizumab is efficacious and safe for the management of extra-large PEDs in treatment-naïve MNV eyes. To better understand brolucizumab's mechanism of action, particularly at the sub-RPE and choroidal levels, and the underlying functional principle for the PED response, more study of the drug's pharmacotherapeutics is warranted.

Macular neovascularization (MNV) is the most common cause of irreversible visual loss in the aged population globally. Pigment epithelial detachment (PED) is one of the earliest biomarkers of MNV and one of the many imaging characteristics of the disease. Sub-retinal pigment epithelial (sub-RPE) fluid, sub-retinal fluid (SRF), intra-retinal fluid (IRF), and hemorrhage can all develop in the presence of PED, serving as additional biomarkers of disease activity. Also, the change from the quiescent form of MNV to the exudative form is linked to the rise in PED height. One year after diagnosis, approximately half of the patients with newly diagnosed PED experience a severe reduction in visual acuity (>3 lines) if they are not treated.,, Moreover, it has been widely reported that sub-RPE fluid persists longer than SRF or IRF.,, Anti-vascular endothelial growth factor (anti-VEGF) therapy remains the standard of care for MNV management, but it has yielded suboptimal outcomes in terms of PED morphology., Brolucizumab (Beovu®; Novartis, Basel, Switzerland), approved recently in 2019, has shown excellent efficacy for MNV, including in refractory cases., In the phase III HAWK and HARRIER trials, brolucizumab outperformed aflibercept in resolving sub-RPE fluid. Here, we describe the role of brolucizumab in the management of extra-large PED (>350 μm) in three eyes with treatment-naïve MNV. Three eyes of three patients with extra-large PED secondary to treatment-naïve MNV who received intravitreal injection (IVI) brolucizumab were included in this prospective, non-randomized, uncontrolled case study performed at a single tertiary center in India. Extra-large PEDs were defined as PEDs with a maximal height exceeding 350 μm. The study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board and the Ethical Committee of the Retina Institute of Bengal, India. Written informed consent was obtained from each patient. The procedure of IVI brolucizumab (6 mg/0.05 ml) was performed in an operating room under aseptic precautions. Topical moxifloxacin 0.5% was advised post-injection for seven days. The patients were reviewed on day 2, week 4, and subsequently 4 weekly after the baseline injection. The clinical evaluation at each visit included best-corrected visual acuity (BCVA) testing using a Snellen chart, intraocular pressure measurements using a Goldmann applanation tonometer, and anterior and posterior segment examinations. Spectral-domain optical coherence was also performed at all visits. Using the built-in calipers, a masked observer (S.C.) measured the PED's maximum height (S.C.). Three monthly loading dose regimen was employed for the patients.

An 81-year-old one-eyed male presented with decreased vision in the left eye (OS) for 15 months. His best-corrected visual acuity (BCVA) was 20/125 in the OS. The patient had an active MNV in the OS with an extra-large PED (Fig. 1a and1b). The patient was administered three monthly IV brolucizumab in the OS. At weeks 4 and 8, his BCVA improved to 20/120, with further improvement to 20/80 at week 12. The PED height also dramatically decreased after 4 weeks (Fig. 1c), resolved entirely after 8 weeks (Fig. 1d), and did not recur after 12 weeks (Fig. 1e). No adverse events were noted during any visit.

A 70-year-old female patient developed a sudden onset of decreased vision in the right eye (OD) for 10 days. Her BCVA was 20/120 in the OD, while it was no PL in the OS. The patient was diagnosed with active MNV with subfoveal bleed and an extra-large PED in the OD (Fig. 2a and b). Following the first dose of IVI brolucizumab, the patient's BCVA improved to 20/32 in the OD, with significant resolution of PED, subretinal fluid (SRF), and subfoveal bleed (Fig. 2c and d) at 4 weeks. Four weeks after the second dose, her BCVA remained stable at 20/32, with complete resolution of the PED, SRF, and subfoveal bleed (Fig. 2e and f). The patient received the third loading dose of IVI brolucizumab and is scheduled for a follow-up. There were no safety concerns with the brolucizumab injection during any of the visits.

A 77-year-old female patient presenting with OS decreased vision and metamorphopsia was diagnosed with active MNV with an extra-large PED (Fig. 3a and b). Her BCVA was 20/20 in the OD and 20/80 in the OS. The patient had bilateral pseudophakia for 10 years. The patient was advised three loading doses of brolucizumab and underwent the first dose in July 2022. At 4 weeks, her BVCA improved to 20/60 with a near-total resolution of the PED (c). No ocular or systemic adverse events were noted. The patient is scheduled for the second dose of brolucizumab.

In our real-world case series, we show that brolucizumab is effective at improving the morphology of the PED in eyes with MNV. The PED resolution was accompanied by an improvement in vision in all three eyes without any safety concerns. PED is a hallmark feature of MNV. It denoted the separation between the inner collagenous layer of the Bruch's membrane and the basal lamina of the RPE. There is still much uncertainty about the specific pathophysiology of PED. It is believed that Bruch's membrane degeneration, which is an indispensable component of the progression of MNV disease, plays a significant role., PED arises when fluid or blood leaks into the sub-RPE compartments due to the proliferation of MNV., It can be encountered in anywhere between 30 and 80% of patients who have MNV. These PEDs can cause progressive vision deterioration if not adequately treated., In addition, complications, including RPE rips and bleeding, may result in an acute loss of vision., Serra et al. investigated the natural history of quiescent MNVs and found that an increase in PED height (>140 μm) is a key indicator of the transformation from the quiescent stage to the exudative form. The PED height was also a significant predictive factor for the visual outcome. Taller PEDs may therefore indicate a more aggressive type of the disease with a higher probability of adverse visual outcomes. Additionally, they are more resistant to anti-VEGF therapy, which is an important cause of suboptimal visual outcomes., To learn more about and explore this aspect, the authors enrolled eyes with extra-large PEDs that were at least 350 μm high in the study and investigated how they responded to treatment with brolucizumab. Currently, the management of PED is complex due to its relative unresponsiveness to anti-VEGF therapy. Previously, aflibercept has shown a good response in treatment-resistant PEDs. In the phase III HAWK and HARRIER trials, visual outcomes at 96 weeks showed that brolucizumab was non-inferior to aflibercept. Furthermore, brolucizumab was more effective than aflibercept in decreasing retinal thickness and clearing fluid from the sub-RPE, subretinal, and intraretinal regions. In a retrospective comparative study, it was demonstrated that brolucizumab was superior to aflibercept in achieving faster resolution of PED, noted as early as 1 month. Similarly, in all three eyes of our study, the PED showed excellent early response, resolving almost completely within four weeks. Additionally, in two of the three eyes, complete resolution was seen within 8 weeks, which was prior to the completion of the three loading doses. Although faster PED resolution has been linked to an increased risk of RPE rip, none of the three eyes in our series showed any signs of this complication, even when the PEDs were extra-large. Due to the small sample size and brief follow-up period in our study, more research is required in this aspect. Brolucizumab's superior outcomes can be attributed to its molecular properties, such as its smaller size of 26 kDa, which enables better penetration across the retinal layers, including the RPE., Also, it helps deliver a higher molar dose of the drug with its ability to bind in a 2:1 ratio with VEGF-A., This allows for greater efficacy as well as durability of the agent when injected into the eye., Tamashiro T et al. have demonstrated that brolucizumab therapy induces considerable alterations in choroidal morphology, which may be greater than those documented previously for other anti-VEGF drugs. Brolucizumab outperformed all anti-VEGF molecules, including the recently FDA-approved faricimab, in terms of BCVA gains and reduction in retinal thickness, in a systematic review and network meta-analysis of anti-VEGF medicines in nAMD. As a result of its greater efficacy compared to other anti-VEGF medications, brolucizumab therapy was initiated in all of our cases, despite the fact that they were all treatment-naive. Indeed, the excellent response of PED observed in our series calls for additional molecular and immunological research to better understand the pharmacodynamics and pharmacokinetics of brolucizumab at the sub-RPE and choroidal levels. Intraocular inflammation (IOI) remains a major concern with the use of brolucizumab. The rate of IOI in the landmark HAWK and HARRIER studies was around 4.4%. However, in the real world, there have been reports of significant variations, ranging from 0% in the BRAILLE study to 12.4% in the SWIFT study., In two large real-world datasets, the IRIS Registry (10,654 eyes) and the Komodo Healthcare Map (11,161 eyes), the rate of IOI was approximately 2.4%. The BRAILLE study is the first real-world data from India to evaluate the safety and effectiveness of brolucizumab in nAMD eyes., In the short-term results, no occurrences of IOI were seen, however in the 52-week data, the incidence was 3.66%., Here, all three patients had mild IOI that resolved completely with topical therapy. The authors suggest looking into how race and genetics may contribute to or protect against brolucizumab-related IOIs., Therefore, taking into consideration the somewhat improved safety profile of brolucizumab in Indian eyes, with the episodes of IOI being restricted to milder episodes, the authors had no reservations in starting all patients on brolucizumab therapy. Even though we did not observe any adverse events, our series was too small, and the follow-up period was too short, to draw any meaningful conclusions. We have limited evidence on the safety and efficacy of brolucizumab in MNV eyes with extra-large PEDs based on only three cases. To get a better understanding of the role that brolucizumab plays in the eyes of this particular subset of MNV patients, additional research with larger sample sizes and longer follow-ups are required.

In this real-world case series, we demonstrate the short-term efficacy of brolucizumab for the management of extra-large PED in treatment-naïve MNV eyes. Further research on the pharmacotherapeutics of brolucizumab is required to better understand its mechanism of action, particularly at the sub-RPE and choroidal levels, and the underlying functional principle for the PED response.

Written informed consent was obtained from patients for publication of these case reports and any accompanying images.

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The following authors have no financial disclosures: SC, JS.