Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion–Related Events with Brolucizumab

Abstract

An independent Safety Review Committee (SRC), supported by Novartis Pharma AG, analyzed investigator-reported cases of intraocular inflammation (IOI), endophthalmitis, and retinal arterial occlusion in the phase 3 HAWK and HARRIER trials of brolucizumab versus aflibercept in neovascular age-related macular degeneration (nAMD).Design: A post hoc analysis of a subset of data from two 2-year, double-masked, multicenter, activecontrolled randomized phase 3 trials (NCT02307682, NCT02434328).Participants: Patients (N ¼ 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye were randomized and treated in HAWK/HARRIER. The SRC reviewed data from cases of investigator-reported IOI (60/1088 brolucizumab-treated eyes; 8/729 aflibercept-treated eyes).Methods: The SRC received details and images (color fundus photography, fluorescein angiography, and OCT) for all investigator-determined cases of IOI, retinal arterial occlusion, and endophthalmitis. Cases were reviewed in detail by !2 readers, then adjudicated by the SRC as a group.Main Outcome Measures: Within this patient subset: incidence of IOI, signs and incidence of retinal vasculitis and/or retinal vascular occlusion, and visual acuity loss; time since first brolucizumab injection to IOI event onset; and frequency of visual acuity loss after brolucizumab injection by time of first IOI event onset.Results: Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI þ vasculitis, 3.3%; IOI þ vasculitis þ occlusion, 2.1%). There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (!15 ETDRS letters) in eyes with IOI (7 in eyes with IOI þ vasculitis þ occlusion). Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first brolucizumab injection (increasing to 7/8 within 6 months). Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%.Conclusions: This analysis of IOI cases after brolucizumab injection identified signs of retinal vasculitis with or without retinal vascular occlusion and an associated risk of visual acuity loss. The findings will help physicians to evaluate the risks and benefits of brolucizumab treatment for nAMD. Ophthalmology 2020;-:1e10

Inflammatory Complications of Intravitreal Anti-VEGF Injections

“…These reports prompted Novartis Pharma AG to assemble an independent safety committee comprised of nine members, two separate external data monitoring committees, and an independent observer from ASRS to conduct a post hoc analysis of the HARRIER and HAWK trials [61]. Their analysis found that of the 1088 eyes treated with brolucizumab from 1088 patients, 36 developed "probable or definite" retinal vasculitis (3.3%).…”

An Overview of Age-Related Macular Degeneration: Clinical, Pre-Clinical Animal Models and Bidirectional Translation

“…Brolucizumab is groundbreaking as it is the first anti-VEFG therapy that has demonstrated similar efficacy from a single injection, 4 times a year [46]. Unfortunately, adoption of Brolucizumab has been limited by intraocular inflammation, vasculitis, and vascular occlusion causing visual decline that was seen in 4.6% of trial participants [52]. Potential adverse effects of anti-VEGF therapies include conjunctival hemorrhage, vitreous hemorrhage, increased intraocular pressure, cataract progression, and, rarely, retinal detachment, infection, and intraocular inflammation [44].…”

Medication-induced Uveitis: An Update

“…[25] About 90% of these cases were mild to moderate, and were treated successfully with topical corticosteroids. [25] In the post-hoc analysis of the HAWK and HARRIER data, Mones et al [26] reported that the incidence of intraocular inflammation was 4.6% in eyes treated with brolucizumab; 3.3% of patients developed retinal vasculitis with occlusive vasculitis in 2.1% of the eyes. [26] In addition, 0.7% of the cases experienced at least moderate vision loss (≥15 ETDRS letters), and most of these events occurred in the first six months of drug use.…”

“…[25] In the post-hoc analysis of the HAWK and HARRIER data, Mones et al [26] reported that the incidence of intraocular inflammation was 4.6% in eyes treated with brolucizumab; 3.3% of patients developed retinal vasculitis with occlusive vasculitis in 2.1% of the eyes. [26] In addition, 0.7% of the cases experienced at least moderate vision loss (≥15 ETDRS letters), and most of these events occurred in the first six months of drug use. In the same study, the incidence of intraocular inflammation in aflibercept-treated eyes was 1.1%, with at least moderate vision loss in 0.14%.…”

“…In the same study, the incidence of intraocular inflammation in aflibercept-treated eyes was 1.1%, with at least moderate vision loss in 0.14%. [26] The mechanism for intraocular inflammation secondary to anti-VEGF injections is not fully understood, but some experts suggest that it is due to the formation of anti-drug antibodies and subsequent hypersensitivity reactions to the medicine. [27]…”