Elsevier

Ophthalmology

Volume 128, Issue 7, July 2021, Pages 1050-1059
Ophthalmology

Original Article
Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion–Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER

Presented at: the Retina Society Annual Meeting, September 21–22, 2020 (Virtual).
https://doi.org/10.1016/j.ophtha.2020.11.011Get rights and content
Under a Creative Commons license
open access

Purpose

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, active-controlled randomized phase 3 trials (NCT02307682, NCT02434328).

Participants

Patients (N = 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 + vasculitis, 3.3%; IOI + vasculitis + 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 + vasculitis + 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.

Keywords

brolucizumab
intraocular inflammation
neovascular age-related macular degeneration
retinal vasculitis
retinal vascular occlusion
retinal arterial occlusion
retinal occlusive vasculitis
safety

Abbreviations and Acronyms

AE
adverse event
CFP
color fundus photography
FA
fluorescein angiography
ETDRS
Early Treatment Diabetic Retinopathy Study
IOI
intraocular inflammation
MedDRA
Medical Dictionary for Regulatory Activities
nAMD
neovascular age-related macular degeneration
SRC
Safety Review Committee
VEGF
vascular endothelial growth factor

Cited by (0)

Supplemental material available at www.aaojournal.org.

Disclosure(s): All authors have completed and submitted the ICMJE disclosures form.

The author(s) have made the following disclosure(s): C.P.: Personal fees – Novartis PHARMA, other from Novartis Pharma, during the conduct of the study; Personal fees and other – Bayer Pharma, Novartis Pharma, Roche Pharma, outside the submitted work.

J.S.H.: Personal fees – 4DMT, Adverum, Aerie, Aerpio, Aldeyra, Allegro, Alzheon, Annexon, Apellis, Asclepix, Aviceda, Beaver-Visitec, DTx, Eloxx, Galimedix, Genentech, Gyroscope, iRenix, jCyte, Kala, Kanghong, NGM, Notal Vision, Novartis, Ocugenix, Oculis, Ocunexus, Ocular Therapeutix, Oxurion, Palatin, Pfizer, Regeneron, Regenxbio, Santen, Scifluor, Shire, Stealth, Thea, Tyrogenex, Vinci, Voyant; Grants – Aerie, Aerpio, Apellis, Genentech, Graybug, Gyroscope, Hemera, Janssen R&D, KalVista, Kanghong, Novartis, Ophthotech, Optovue, Regeneron, Regenxbio, Stealth, outside the submitted work.

I.K.K.: Personal fees – Novartis, during the conduct of the study; Personal fees – Kodiak Sciences; Nonfinancial support – Allergan; Personal fees – Biophytis and Castle Biosciences, outside the submitted work.

J.M.: Grants and personal fees – Novartis, Alcon, Roche, Bayer, Apellis, Kodiak Sciences, Reneuron, Genentech; Grants, Personal fees, and other – Iveric Bio; Personal fees – Cellcure, Lineage Cell Therapeutics, Maculogix; Personal fees and other – Notal Vision; outside the submitted work.

F.H.: Novartis; during the conduct of the study; Apellis, Heidelberg Engineering, Zeiss, Acucela, Genentech/Roche, Allergan, Boehringer-Ingelheim, Bayer Healthcare, LIN Bioscience, Pixium, Kanghorn, Oxurion, Grayburg Vision, Stealth BioTherapeutics, Geuder; outside the submitted work.

J.F.K.: Personal fees – Bayer, Novartis, Kanghong, Roche, Allergan, Thea; outside the submitted work. R.T.: Personal fees – Novartis, during the conduct of the study; Grants and personal fees – Novartis, Bayer; Personal fees – Alcon; Nonfinancial support – Zeiss; Personal fees –Genentech, Roche, Allergan, Thea, Oculis, outside the submitted work.

T.M.: no relevant conflicts. S.K.S.: Personal fees – Novartis, during the conduct of the study; Grants and personal fees – Novartis, Regeneron; Personal fees – Zeiss; Grants and personal fees – Bausch + Lomb, Eyepoint; Personal fees – Clearside; Grants – Santen; Personal fees – RegenerxBio, from null, outside the submitted work.

G.J.J.: Personal fees – Novartis, during the conduct of the study; Personal fees – Novartis, Iveric, Regeneron, EyePoint, outside the submitted work.

T.A.A.: Personal fees – Novartis, during the conduct of the study; Personal fees – Novartis, outside the submitted work.

P.K.K.: Personal fees – Bayer, Regeneron, Allergan, Novartis; Nonfinancial support – Carl Zeiss Meditec; Personal fees – Kanghong, Kodiak, Formycon/BioEq, outside the submitted work.

Novartis Pharma AG funded the original phase 3 HAWK and HARRIER clinical trials, the expenses of the SRC analysis, and the medical writing support for this manuscript. The autonomy of the SRC was established upfront via a charter; as such, the SRC selected the cases and data to review, completed the analysis and assessment of relevant reports, and agreed as a group the conclusions reported. Novartis did not influence the findings and was not involved in the development of this manuscript. Novartis completed quality checks of the manuscript for accuracy but did not recommend any material changes to the content. All authors provided full approval of the final manuscript as submitted to Ophthalmology.

Selected data have been published via brolucizumab.info and made available to relevant societies, including the Macula Society, American Academy of Ophthalmology, American Society of Retina Specialists, Retina Society, Japanese Retina Vitreous Society, and EURETINA.

HUMAN SUBJECTS: Human subjects were included in this post hoc analysis. Protocols were approved by an Independent Ethics Committee/Institutional Review Board. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent.

No animal subjects were used in this study.

Author Contributions:

Conception and design: Monés, Srivastava, Jaffe, Tadayoni, Albini, Kaiser, Holz, Korobelnik, Kim, Pruente, Murray, Heier

Data collection: Monés, Srivastava, Jaffe, Tadayoni, Albini, Kaiser, Holz, Korobelnik, Kim, Pruente, Murray, Heier

Analysis and interpretation: Monés, Srivastava, Jaffe, Tadayoni, Albini, Kaiser, Holz, Korobelnik, Kim, Pruente, Murray, Heier

Obtained funding: N/A

Overall responsibility: Monés, Srivastava, Jaffe, Tadayoni, Albini, Kaiser, Holz, Korobelnik, Kim, Pruente, Murray, Heier