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

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

Research output: Contribution to journalArticle

96 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)72-84
Number of pages13
JournalOphthalmology
Volume127
Issue number1
DOIs
StatePublished - Jan 2020

Keywords

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

ASJC Scopus subject areas

  • Ophthalmology

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