HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration

doi:10.1016/j.ophtha.2020.06.028

Ophthalmology

Volume 128, Issue 1, January 2021, Pages 89-99

Presented at: American Academy of Ophthalmology Annual Meeting, October 2018, Chicago, Illinois.

https://doi.org/10.1016/j.ophtha.2020.06.028 Get rights and content

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Purpose

To report the 96-week outcomes from HAWK and HARRIER.

Design

Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with neovascular age-related macular degeneration (nAMD).

Participants

Treatment-naïve eyes with nAMD were randomized 1:1:1 to brolucizumab 3 mg (n = 358), brolucizumab 6 mg (n = 360), aflibercept 2 mg (n = 360; HAWK) or 1:1 to brolucizumab 6 mg (n = 370), aflibercept 2 mg (n = 369; HARRIER).

Methods

After 3 monthly loading doses, brolucizumab patients received every (q)-12-week (w) dosing, possibly adjusting to q8w dosing if disease activity was present at predefined disease activity assessment (DAA) visits. Aflibercept was dosed in a fixed q8w regimen. Visual and anatomic parameters were assessed throughout. Primary end point was at week 48 (48w), confirmed at 96w.

Main Outcome Measures

Mean best-corrected visual acuity (BCVA) change from baseline, proportion of patients on an q12w regimen, retinal thickness, retinal fluid changes, and safety, all to 96w.

Results

Mean change (least squares [LS] mean ± standard error) in BCVA from baseline to 96w in HAWK was 5.6±0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90±0.78 letters for brolucizumab 6 mg, and 5.3±0.78 letters for aflibercept and in HARRIER was 6.1±0.73 letters for brolucizumab 6 mg and 6.6 ± 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, −174.8 μm vs. −148.7 μm; 95% confidence interval for treatment difference, –46.2 to –5.9 μm; P = 0.0115) and HARRIER (LS mean, –197.7 μm vs. –155.1 μm; 95% confidence interval for treatment difference, –62.0 to –23.3 μm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P = 0.0688) and 24% (P = 0.0002) for brolucizumab 3 mg and 6 mg and 37% for aflibercept, whereas in HARRIER, they were 24% for brolucizumab 6 mg (P < 0.0001) and 39% for aflibercept. At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively. Brolucizumab exhibited an overall well-tolerated safety profile.

Conclusions

Visual outcomes from 48w to 96w confirm the efficacy achieved at 48w. Brolucizumab demonstrated greater fluid resolution compared with aflibercept. The q12w potential for brolucizumab observed at 48w was maintained to 96w.

Abbreviations and Acronyms

adverse event

ATE

arterial thromboembolic event

BCVA

best-corrected visual acuity

CST

central subfield thickness

DAA

disease activity assessment

ETDRS

Early Treatment Diabetic Retinopathy Study

IOI

intraocular inflammation

IRF

intraretinal fluid

least squares

nAMD

neovascular age-related macular degeneration

RAO

retinal artery occlusion

RPE

retinal pigment epithelium

SAE

serious adverse event

SRF

subretinal fluid

VEGF

vascular endothelial growth factor

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: 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): P.U.D.: Consultant – Bausch & Lomb Pharma, Genentech, Alcon Surgical, Alcon Pharmaceutical, NeoVista, MacuSight, ArticDx, ORA, Novartis, Allergan, Santen, Inc., Thrombogenics, Ophthotech, Lux BioScience, DigiSight, Roche, TopCon, Acucela, Pentavision, ORA, Stealth Biotherapeutics, Annidis, Clearside Biomedical, Optovue, Pentavision, Neurotech, Lutronic, Alimera Sciences, DOSE Medical, Aerpio, Omeros, Shire Human Genetics, Opthea, Spark Thereapeutics, Graybug Vision, Zeiss Group, Irenix, ByeOnics, Clearside Biomedical, PanOptica, Chengdu Kanghong Biotechnology, SciFluor Life Sciences, Boehringer Ingelheim, Kodiak Sciences Oculis SA, pSivida Corporation Amgen, Aerie Pharmaceutical; Scientific advisory board – Alcon Surgical (RACII), Genentech, MacuSight, Novartis, NeoVista, ArticDX, Alcon Pharmaceutical, AMO, Thrombogenics, Santen, Ophthotech, Lux BioScience, Digisight, Roche, Acucela, Stealth Biotherapeutics, Lutronic, Avalanche, TrueVision, Alimera Sciences, Orbis International, Annidis, Neurotech, Aerpio, DOSE Medical, Omeros, Shire Human Genetics, Opthea, Graybug Vision, CDR-Life, Inc., Clearside Biomedical; Equity owner – Alimera Sciences, Aerpio, Annidis, ArctixDx, Digisight, Irenix, Ophthotech, Clearside Biomedical, PanOptica

: R.P.S.: Consultant – Novartis, Genentech/Roche, Alcon, Regeneron, Bayer, Optos, Genentech; Financial support – Apellis

: A.K.: Consultant – Novartis, Bayer, Allergan, Carl Zeiss Meditec, Heidelberg Engineering

: Y.O.: Financial support – Novartis Pharma, Bayer, Senju, Kowa, Wakamoto, Hoya, Santen

: G.W.: Employee – Novartis Pharmaceuticals

: K.G.: Employee – Novartis Pharmaceuticals

: G.J.J.: Financial support – Alcon/Novartis, Sanofi, Heidelberg Engineering, Novartis, pSivida, Regeneron

: R.T.: Consultant – Alcon, Allergan, B+L, Bayer, FCI, Genentech, Novartis, Roche, Thea, Thrombogenics, Zeiss

: U.S.-E.: Financial support – Novartis, Genentech, Novartis, Boehringer, Roche

: F.G.H.: Consultant – Heidelberg Engineering, Zeiss, Acucela, Genentech/Roche, Allergan, Boehringer-Ingelheim, Bayer Healthcare, LIN Bioscience, Pixium, Chengdu Kanghong; Financial support – Novartis, Nightstar, Optos, Heidelberg Engineering, Carl Zeiss Meditec, Allergan, Roche/Genentech, Pixium; Lecturer – Roche/Genentech, Zeiss, Heidelberg Engineering, Bayer Healthcare.

: Supported by Novartis Pharma AG, Basel, Switzerland. The sponsor or funding organization participated in the design of the study; management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.

: HUMAN SUBJECTS: Human subjects were included in this study. This multicenter trial was conducted in 408 sites in North, Central, and South America; Europe; Asia; Australia; and Japan. All patients provided written informed consent. Protocols were approved by an Independent Ethics Committee/Institutional Review Board. Trials were conducted in accordance with principles of the Declaration of Helsinki, International Conference on Harmonization E6 Good Clinical Practice Consolidated Guideline, and other regulations as applicable and were compliant with the Health Insurance Portability and Accountability Act of 1996. All patients provided written informed consent.

: No animal subjects were included in this study.

: Author Contributions:

: Conception and design: Weissgerber

: Analysis and interpretation: Dugel, Singh, Koh, Ogura, Weissgerber, Gedif, Jaffe, Tadayoni, Schmidt-Erfurth, Holz

: Data collection: Dugel, Singh, Koh, Ogura, Weissgerber, Gedif, Jaffe, Tadayoni, Schmidt-Erfurth, Holz

: Obtained funding: N/A

: Overall responsibility: Dugel, Singh, Koh, Ogura, Weissgerber, Gedif, Jaffe, Tadayoni, Schmidt-Erfurth, Holz

© 2020 by the American Academy of OphthalmologyThis is an open access article under the CC BY-NC-ND license (<inter-ref xlink: href=http://creativecommons.org/licenses/by-nc-nd/4.0/>http://creativecommons.org/licenses/by-nc-nd/4.0/</inter-ref>).