HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.

Abstract

PURPOSE:

Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD).

DESIGN:

Double-masked, multicenter, active-controlled, randomized trials.

PARTICIPANTS:

Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye.

INTERVENTION:

Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing.

MAIN OUTCOME MEASURES:

The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes.

RESULTS:

At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mg-treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P = 0.001) and HARRIER (22.7% vs. 32.2%; P = 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean -172.8 μm vs. -143.7 μm; P = 0.001) and HARRIER (LS mean -193.8 μm vs. -143.9 μm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept.

CONCLUSIONS:

Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (ClinicalTrials.gov; NCT02307682, NCT02434328).

• Authors: Pravin U Dugel, Adrian Koh, Yuichiro Ogura, Glenn J Jaffe, Ursula Schmidt-Erfurth, David M Brown, Andre V Gomes, James Warburton, Andreas Weichselberger, Frank G Holz, HAWK and HARRIER Study Investigators
• Journal: Ophthalmology (Ophthalmology) Vol. 127 Issue 1 Pg. 72-84 (01 2020) ISSN: 1549-4713 [Electronic] United States
• PMID: 30986442 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal, Humanized
• Recombinant Fusion Proteins
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• aflibercept
• Receptors, Vascular Endothelial Growth Factor
• brolucizumab

Topics

• Aged
• Aged, 80 and over
• Angiogenesis Inhibitors (adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Choroidal Neovascularization (drug therapy, physiopathology)
• Double-Blind Method
• Female
• Humans
• Intravitreal Injections
• Male
• Middle Aged
• Receptors, Vascular Endothelial Growth Factor (therapeutic use)
• Recombinant Fusion Proteins (adverse effects, therapeutic use)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)
• Visual Acuity (physiology)
• Wet Macular Degeneration (drug therapy, physiopathology)