Investigating inflammation caused by intravitreal brolucizumab

Preexisting neutralizing antibodies associated with the inflammatory changes.

This article was reviewed by Thomas Albini, MD.

The clinical trials of brolucizumab (Beovu, Novartis), HAWK and HARRIER1 reported highly promising findings regarding the drug’s safety and efficacy, including noninferiority to aflibercept (Eylea, Regeneron Pharmaceuticals), reduced injection frequencies, and improved secondary imaging outcomes. In addition, the overall safety data were good and the drug was subsequently approved by the FDA.

However, shortly after physicians began using brolucizumab in clinical settings, cases of intravitreal inflammation associated with occlusive retinal vasculitis and severe visual acuity loss in a few patients were being reported in early 2020. The American Society of Retina Specialists reported 26 cases and closer evaluations showed arterial, venous, choroidal, optic nerve, and anterior segment inflammation, and vitritis.

A closer look

Baumal et al reported on 15 eyes of 12 patients treated with intraocular brolucizumab injections; the mean vision decreased in these patients from 20/53 to 20/2002 and the findings included vitreous and anterior chamber cells, nongranulomatous granular precipitates, retinal artery changes, vascular leakage, occlusion, ischemia, dilated retinal veins, and optic nerve leakage, according to Thomas Albini, MD, professor of ophthalmology at Bascom Palmer Eye Institute in Miami, Florida.

Novartis assembled an expert committee to review all ocular imaging and cases of inflammation from the HAWK and HARRIER studies. A rate of intraocular inflammation of about 4.6% was ascertained in the patients in the HAWK and HARRIER studies; 3.3% had intraocular inflammation and retinal vasculitis; 2.1% had intraocular inflammation with retinal vasculitis and occlusion; and 0.5% had these findings associated with severe vision loss, Albini said.

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“This resulted in about a 1 in 200 chance of retinal vasculitis with occlusion and severe vision loss,” according to the HAWK and HARRIER data, Albini said.

Every aspect of the drug and its administration were examined, including patient risk factors. Aggressive treatment was recommended in patients with ocular inflammation, especially vasculitis, with systemic or local steroids.

Further studies by Michael Ip, MD, and Marco Zarbin, MD, using data from the IRIS Registry and Komodo claims registry, identified an association between female gender and retinal vasculitis and with a history of previous inflammation.

“Any previous inflammation seemed to predispose these patients to retinal vascular events,” he advised. “When using brolucizumab, patients must be asked about, for example, prior HLA B27-associated uveitis.”

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Albini explained that it is not unusual for treatment-naïve patients to have pre-existing antibodies to anti-VEGF agents. However, the numbers are generally low. When the HAWK and HARRIER data were evaluated, investigators found higher values than those typically seen, about 40%. There was a risk of either having preexisting antidrug antibodies, specifically neutralizing antibodies, or a having a boost in the antibodies during the trial that would be associated with an inflammatory vascular event, indicating that this could be an immunologic phenomenon.

“The finding was that 86% of patients with retinal vasculitis and retinal occlusion had neutralizing antibody positivity either at baseline or were boosted during the study,” he said.

Baumal and colleagues also reported a 24-week study3 of 172 eyes treated with brolucizumab injections. The investigators found that 8.1% of patients had intraocular inflammation and 1 patient had severe VA loss associated with retinal vasculitis. The study also showed an inflammation rate of 1 in 200 patients and a correlation with female gender. However, no association was found between the injections and previous inflammation.

References
1. Dugel P, 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. Ophthalmology. 2020;127(1):72-84. doi:10.1016.j.opht ha.2019.04.017
2. Baumal CR, Spaide RF, Vajzovic L, et al. Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. Ophthalmology. 2020;127(10):1345-1359. doi:10.1016/j.ophtha.2020.04.017
3. Baumal CR, Bodaghi B, Singer M, et al. Expert opinion on management of intraocular inflammation, retinal vasculitis, and vascular occlusion after brolucizumab treatment. Ophthalmol Retina. Published online September 19, 2020. 2020;S2468-6530(20)30400-0. doi:10.1016/j. oret.2020.09.020
Thomas Albini, MD
E: talbini@med.miami.edu
This article is adapted from Albini’s presentation at the Bascom Palmer Angiogenesis, Exudation, and Degeneration 2021 virtual meeting. Albini is a consultant to Novartis and is on the company’s data monitoring committee and safety review committee.

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