Rod McNeil; Reviewed by Dr David S. Boyer, Prof. Ramin Tadayoni, Dr Jeffrey S. Heier and Dr Paul Hahn

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Two Phase 3 clinical trials, HAWK and HARRIER, demonstrated that brolucizumab (Beovu, Novartis) is an effective treatment for neovascular age-related macular degeneration (nAMD), demonstrating non-inferiority to aflibercept (Eylea, Bayer/Regeneron) in visual function at week 48 and more favourable retinal fluid outcomes than those seen with aflibercept (see Table 1)

 However, although the safety profiles of the two drugs were found to be similar, intraocular inflammation and ocular occlusive events were more frequently reported with bolucizumab.

In 2020, Novartis carried out a post-marketing safety review of the drug and, along with an independent external safety review committee, concluded that it can cause retinal vasculitis and/or retinal vascular occlusion, which may result in severe vision loss. Typically, these adverse events occur in the presence of intraocular inflammation.

The unmasked post hoc assessment of brolucizumab-treated patients in HAWK and HARRIER showed that the overall rate of intraocular inflammation, retinal vasculitis and concomitant retinal vasculitis and retinal vascular occlusion was 4.6%, 3.3% and 2.1%, respectively.

 The overall rate of developing intraocular inflammation of any form and losing 15 or more letters was 0.74%.

 This compares with an incidence of intraocular inflammation of 1.1% in aflibercept-treated eyes, with at least a moderate visual acuity loss seen in 0.14%.

Safety-related product label updates for brolucizumab have now been approved by several health authorities in Europe, the United States, Canada, Australia and Japan, incorporating the additional information that retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with its use.

 The product’s summary of product characteristics states that in patients developing these conditions, treatment with brolucizumab should be discontinued and the events promptly managed.Physicians are also advised to ensure provision of clear information to patients, establish an appropriate control plan and confirm absence of inflammation prior to re-injection.

The true incidence of vaso-occlusive events following brolucizumab administration remains unknown. Post-marketing data for cases reported through to 18 December 2020 indicate a total incidence of 15.73 of the three adverse events of interest for every 10,000 (distributed) injections, with combined retinal vasculitis and retinal vascular occlusion being the most prevalent at 7.46 per 10,000 injections.

Despite the risk of potentially serious adverse events seen with brolucizumab, events that are not commonly associated with intravitreal anti-vascular endothelial growth factor (VEGF) agents,

 rates of moderate and severe vision loss were similar for brolucizumab and aflibercept in the HAWK and HARRIER registration trials (Table 2).

 Asked under what circumstances physicians consider using brolucizumab for nAMD, Dr David S. Boyer, Retina-Vitreous Associates Medical Group, Los Angeles, California, United States, commented: “The HAWK and HARRIER trials confirmed the outstanding drying effects of brolucizumab compared with aflibercept.”

He added: “Unfortunately, the safety of brolucizumab will limit use as a first line therapy, delegating its use to patients who do not respond at all, or are very poor responders to the currently available anti-VEGF treatments. I am hoping that the uveitis and vaso-occlusive retinal issues can be mitigated by Novartis to allow a safer drug safety profile, thereby allowing more widespread use of brolucizumab.”

Speaking at the 20th EURETINA virtual congress, Prof. Ramin Tadayoni, Universite de Paris, Lariboisiere, Saint Louis and Fondation Adolphe de Rothschild Hospitals, Paris, France, said that brolucizumab represents an important treatment option for patients with nAMD, with an overall favourable benefit/risk profile, in particular in patients uncontrolled with other intraocular anti-VEGF therapies.

 He added that the product addresses key unmet needs for patients with nAMD by providing robust vision gains and favourable anatomic outcomes with the potential to extend treatment intervals.

Describing his views on the use of brolucizumab for nAMD, Prof. Tadayoni said: “Brolucizumab is of particular interest when the physician thinks he can better control the disease with this molecule than with other anti-VEGFs. Once patients are carefully selected, the prerequisite is to obtain appropriate informed consent and provide clear education about which signs should lead to a rapid consultation, especially any inflammation following brolucizumab. The more we learn about how to control and treat rare but potentially serious ocular adverse events after brolucizumab injection, the more real-life use would extend.”

Through the Novartis-lead Brolucizumab Coalition partnership, which incorporates a multidisciplinary internal team and external global experts, key questions are being raised to try to better characterise adverse events of interest associated with brolucizumab and mitigate the risk of patients developing retinal vasculitis and/or retinal vascular occlusion. Preliminary investigations by the Coalition suggest that treatment-emergent anti-drug antibodies (boosted and induced) may be associated with an increased incidence of retinal vasculitis and/or retinal vascular occlusion.

Initial descriptive findings, presented by Dr Jeffrey S. Heier, Ophthalmic Consultants of Boston, US, at the American Academy of Ophthalmology (AAO) 2020 Virtual Retina Subspecialty Day meeting, showed that 86% of patients with at least one retinal vasculitis and/or retinal vascular occlusion event in HAWK and HARRIER were neutralising antibody-positive at baseline (29%) and/or post-baseline (57%).

Neutralising antibodies are a specific type of anti-drug antibody which block the ability of brolucizumab to bind to VEGF. Additional analyses from ongoing brolucizumab trials will help further assess these findings.

Meanwhile, analyses of real-world brolucizumab data (n=10,654 patient eyes from the AAO IRIS Registry) suggest that the observed risk for retinal vasculitis and/or retinal vascular occlusion is increased in patients with prior intraocular inflammation and/or prior vascular occlusion.

 In this large real-life cohort, the majority of patients (91%) who started receiving brolucizumab were switched from a prior anti-VEGF agent.

Post-approval analysis demonstrates that brolucizumab can be associated with intraocular inflammation with or without associated retinal vasculitis and some cases are associated with vision loss, noted Dr Paul Hahn, NJRetina, New Jersey, US and Chair of the ASRS Research & Safety in Therapeutics (ReST) Committee, presenting an update on brolucizumab-related inflammation at the AAO 2020 Virtual Retina Subspecialty Day.

Intraocular inflammation alone may often be managed with topical steroids but the optimal treatment strategy for vasculitis remains unknown, Dr Hahn said. Treatment likely involves steroids, with route of delivery titrated according to severity of findings.

The ASRS ReST Committee recommends that informed consent should discuss the benefit vs risk profile based on available information and patient selection should consider the altered risk profile.

 Physicians should undertake careful examination for inflammation prior to every brolucizumab injection, discuss appropriate warning signs with a low threshold for clinic visit and ensure close follow-up with any issues. Caution is advised when considering brolucizumab treatment in monocular patients or when bilateral injections are indicated, due to the potentially severe nature of the consequences of retinal vasculitis.


Dr Boyer is consultant to several companies including Bayer, Novartis Ophthalmics and Regeneron Pharmaceuticals.


Prof. Tadyoni is an advisor for Novartis, Bayer, Allergan, Roche, Genentech, Oculis, Thea, Alcon and Zeiss.


Dr Heier is a consultant to several companies including Novartis and Regeneron. He is a clinical trial investigator on studies sponsored by several companies including Bayer, Novartis and Regeneron.


Dr Hahn is a consultant/speaker for Genentech and consultant for Alimera and Allergan.

Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER Study Investigators. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. 

Dugel PU, Singh RP, Koh A, et al. HAWK and HARRIER: 96-week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration. 

US FDA Drug Approval Package: Beovu (brolucizumab-dbII). Medical Review. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761125Orig1s000MedR.pdf

European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Beovu: European Public Assessment Report. 12 December 2019. Available at: https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf

Monés J, Srivastava SK, Jaffe GJ, et al. Risk of inflammation, retinal vasculitis, and retinal occlusion-related events with brolucizumab: post hoc review of HAWK and HARRIER. 

Novartis provides update on use and safety of Beovu (brolucizumab). Updated: January 14, 2021. Available at: https://www.brolucizumab.info

Rosenfeld PJ, Browning DJ. Is this a 737 Max moment for brolucizumab? 

Tadayoni R, Nimmerjahn F, Brown D, et al. Investigating adverse events of intraocular inflammation with retinal vasculitis and/or retinal vascular occlusion in patients treated with brolucizumab. Presentation at: 20th European Society of Retina Specialists Virtual Congress, 2-4 October, 2020.

Heier JS. Assessing characteristics of patients with or without intraocular inflammation (IOI) in the brolucizumab treatment arms from the HAWK and HARRIER, phase 3 studies. Presentation at: American Academy of Ophthalmology 2020 Virtual Annual Meeting, 13-15 November, 2020.

Ip M. The brolucizumab experience thus far: a health economics and outcomes research analysis. Presentation at: American Academy of Ophthalmology 2020 Virtual Annual Meeting, 13-15 November, 2020.

Hahn P. Update on brolucizumab-related inflammation. Presentation at: American Academy of Ophthalmology 2020 Virtual Annual Meeting, 13-15 November, 2020.

Witkin AJ, Hahn P, Murray TG, et al. Occlusive retinal vasculitis following intravitreal brolucizumab. 

Articles

Although the majority of patients experience benefit with brolucizumab for the treatment of nAMD without severe adverse events, the risk of retinal vasculitis and/or retinal vascular occlusion needs to be balanced with potential benefits.

Author | Rod McNeil; Reviewed by Dr David S. Boyer, Prof. Ramin Tadayoni, Dr Jeffrey S. Heier and Dr Paul Hahn

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