Brolucizumab in polypoidal choroidal vasculopathy

KEYWORDS:

• Brolucizumab
• IPCV
• Efficacy
• Safety

1. Brolucizumab

Brolucizumab (Beovu, Novartis, Basel, Switzerland) is an anti-vascular endothelial growth factor (anti-VEGF) drug, which was approved for the treatment of neovascular age-related macular degeneration by the United States Food and Drug Administration (US-FDA) on 7 October 2019. It was also approved by the European medical agency (EMA) on 17 February 2020. Brolucizumab received regulatory approval based on the two pivotal phase 3 clinical trials – HAWK and HARRIER, with a q8/q12week dosing regimen [1]. Brolucizumab has a molecular design with a low molecular weight that allows higher molar concentration in the same volume compared to the previous anti-VEGF agents [2]. It has demonstrated the ability to penetrate better in the deeper layers of the retina. Polypoidal choroidal vasculopathy (PCV) is predominantly a Type 1 macular neovascularization in which lesions are located under the retinal pigment epithelium (RPE) and above the Bruch’s membrane. Theoretically, brolucizumab should be able to provide superior regression of lesions in sub-RPE location including PCV. HAWK and HARRIER results did show better sub-RPE fluid control with brolucizumab compared to aflibercept [1]. The use of brolucizumab has been restricted due to its association with intraocular inflammation (IOI). There has been discussion on various virtual scientific platforms if brolucizumab could be an option for PCV cases in the recent times as there is global deficiency of visudyne leading to the nonavailability of photodynamic therapy (PDT) as a treatment option [3]. However, it is yet to be seen if PCV could be one of the indications where the risk–benefit ratio will favor brolucizumab. There are only five studies that have assessed the efficacy and safety of brolucizumab in PCV cases in the recent past. Most of the studies are from the Japanese population except for one study which is from India [4–8] (Table 1). In this index manuscript, we will assess the role of brolucizumab in cases of PCV based on the available evidence.

Table 1. Outcomes of studies with brolucizumab use in polypoidal choroidal vasculopathy.

Study	Reference	Study Design	Total PCV Eyes	Efficacy			Treatment naïve/Resistant/Both	Polyp Regression (%)	Monthly Loading Doses	Inflammation (%)
				BCVA	CMT	CCT
Matsumoto et al.	[4]	Retrospective	19	0.24 ± 0.27 at baseline to 0.12 ± 0.23 after 3 months (P < 0.001)	301 ± 110 μm at baseline to 160 ± 49 μm after 3 months (P < 0.001)	Central choroidal thickness was 264 ± 89 μm at baseline and decreased significantly to 223 ± 81 μm after 3 months (P < 0.001)	Treatment naive	78.9	Yes	19% (Iritis, vitritis, retinal vasculitis, retinal vascular occlusion and papillitis)
Fukuda et al.	[5]	Retrospective	14	0.27 ± 0.34 (log MAR unit) at baseline to 0.20 ± 0.24 at 3-month visit (P < 0.21)	Central retinal thickness significantly decreased by 43%−44%	Subfoveal choroidal thickness also significantly decreased by 20.5%	Treatment naive	78.6	Yes	14.3% (Anterior segment inflammation and arteriolar Occlusion)
Ogura et al.	[6]	Prospective randomized double masked	39	Mean change in BCVA (ETDRS letters) from baseline to week 48/week 96 was+10.4/+11.4	At week 48, the mean central subfoveal thickness reduction was 149 (±17) μm. Maintained till 96 weeks	NA	Treatment naive	NA	Yes	15.4% (Uveitis, iritis, anterior chamber inflammation, retinal artery occlusion and retinal perivascular sheathing)
Ito et al.	[7]	Retrospective	17	Mean BCVA improved significantly from 0.28 at baseline to 0.13 (P < 0.05) at 1 year	The CMT decreased significantly from 421 ± 53 μm before the initial treatment to 206 ± 18 μm (P < 0.01) at 1 year	The CCT decreased significantly from 226 ± 35 μm before the initial treatment to 181 ± 30 μm (P < 0.01) at 1 year	Treatment naive	93.3	Yes	Vitreous haze and vascular sheathing
Chakraborty et al.	[8]	Retrospective	21	The median pretreatment vision was 0.6 logMAR (IQR = 0.47–1 logMAR) and improved to 0.3 logMAR (IQR = 0.25–0.6 logMAR)	The mean macular thickness improved from 443 ± 60 μm at baseline to 289 ± 25 μm (P < 0.001) at the last follow-up period	NA	Both	NA	No	No cases reported with intraocular inflammation

PCV, polypoidal choroidal vasculopathy; BCVA, best-corrected visual acuity; CMT, central macular thickness; CCT, central choroidal thickness; ETDRS, early treatment diabetic retinopathy study; NA, not available.

1.1. Efficacy

Brolucizumab has demonstrated positive efficacy in the management in all five studies. Matsumoto et al. found improved best-corrected visual acuity (BCVA), central macular thickness (CMT), and central choroidal thickness (CCT) along with dry macula that was achieved in 94.4% of the cases after the loading phase [4]. Similarly, Fukuda et al. also demonstrated improvement in all the three parameters mentioned above [5]. Ogura et al. demonstrated significant letter gain and reduction in macular thickness at 48 weeks which was sustained till 96 weeks. Furthermore, resolution of fluid was noted in all the compartments [6]. Ito et al. have also demonstrated significant improvement in BCVA, CMT, and CCT [7]. Chakraborty et al. had more pretreated cases and have shown improvement in BCVA and CMT [8].

1.2. Polypoidal regression

Matsumoto et a.l, Fukuda et al., and Ito et al. assessed polypoidal regression, and it was found to be significantly high in 78.9%, 78.6%, and 93.3% of cases, respectively [4,5,7]. In the study by Ogura et al., it was not possible to evaluate the effect of brolucizumab on polypoidal regression as indocyanine green angiography was performed only at screening [6]. Similarly, Chakraborty et al. have also not evaluated polypoidal closure rate [8].

1.3. Safety

Significant inflammation post-injection was noticed in about 11.8–19% of cases in these studies (Table 1). In the study by Matsumoto et al., all the cases developed IOI within the loading dose period after the second or third injection and were successfully treated with subtenons triamcinolone acetonide (30 mg/0.75 ml) and 0.1% betamethasone drops [4]. In the study by Fukuda et al., one patient with arteriolar occlusion had permanent field loss, while others recovered without any sequelae [5]. The study by Ogura et al. also did not have moderate-to-severe vision loss in cases with IOI and was managed as per standard guidelines [6]. Similarly, both the cases of IOI in the study by Ito et al. resolved after treatment without visual acuity loss [7]. No IOI was reported in the series by Chakraborty et al. After analyzing all five studies, the overall IOI rates seem to be much higher than the other data. It is difficult to hypothesize the reason for the same. One probability is that most of these studies are from the Japanese population and ethnicity could have played a role as there was no IOI reported from the study in India [8]. Furthermore, these cases had monthly injections except the study by Chakraborty et al. in which patients were treated with the pro-re-nata approach where no IOI was reported [8]. However, the possibility of subtle peripheral retinal vasculitis which sometimes goes undetected as it happened in HAWK and HARRIER cannot be ruled out in the series by Chakraborty et al. [8].

1.4. Fluid regression

Analyses of these five studies do indicate that brolucizumab led to robust drying with a possibility of an extended treatment regime. Nearly 80–90% of polypoidal regression is promising and is much higher than the other anti-VEGFs (ranibizumab – 30%, aflibercept –50%) and combination therapy with PDT and anti-VEGF (69.3%) [9]. The high rate of success in choroidal pathology regression is probably due to high molar concentration and better penetration of smaller molecules.

2. Summary

To summarize, with the limited studies available to date, brolucizumab is successful in higher polypoidal regression in cases of PCV. However, significant inflammation is a concern. The FALCON trial results would be able to guide us as to whether a 12 weekly dosing regime from initiation can be of help in reducing the incidence of IOI significantly [10]. If that is achieved, then probably brolucizumab could be a potent treatment option for the management of PCV.

3. Expert opinion

The retinal physicians have options of treating PCV with either combination therapy (PDT and anti-VEGF) or with anti-VEGF monotherapy. However, existing monotherapy increases the injection burden and does not achieve adequate polypoidal regression. Highly potent newer molecules such as brolucizumab that potentially penetrate better at the site where polypoidal lesions are commonly located might change the traditional approach of combination therapy. Inflammation though not very high but has been a challenge for brolucizumab success. Based on the limited available evidence, avoiding loading doses and treating these patients with a pro-re-nata approach from the initial stages might be helpful and the risk–benefit ratio might sway more toward benefit in this subset of PCV, particularly in the resistant cases when the world is facing the absence of PDT as a treatment modality. However, more evidence from randomized controlled trials are needed to establish this approach.

Declaration of interest

A Sharma has acted as a consultant for Novartis, Allergan, Bayer and Intas. BD Kupperman has performed clinical research for Alcon, Alimera, Allegro, Allergan, Apellis, Clearside, Genentech, GlaxoSmithKline, Ionis, jCyte, Novartis, Regeneron, and ThromboGenics and has acted as a consultant for Alimera, Allegro, Allergan, Cell Care, Dose, Eyedaptic, Galimedix, Genentech, Glaukos, Interface Biologics, jCyte, Novartis, Ophthotech, Regeneron, Revana, and Theravance Biopharma. BD Kupperman also acknowledges an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute at the University of California, Irvine. A Loewenstein reports involvement with Allergan, Novartis, Roche, Notal Vision, Forsightslabs, Beyeonics and Bayer Health Care. F Bandello has acted as a consultant for Allergan, Bayer, Boehringer Ingelheim, Fidia Sooft, Hofmann la Roche, Novartis, NTC Pharma, Sifi, ThromboGenics and Zeiss. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received honorarium from Bayer, Novartis and Roche for consultancy and lecture fees. Another reviewer on this manuscript has disclosed that they work in industry on a competing anti-VEGF program. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

A Sharma: conception, analysis, drafting, integrity check, final approval. N Parachuri, N Kumar, BD Kupperman, A Loewenstein, and F Bandello: drafting, revision, analysis, integrity check.

Additional information

Funding

This paper was not funded.