Dr. Pravin U. Dugel – HAWK and HARRIER: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration

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Pravin U. Dugel, Adrian Koh, Yuichiro Ogura, Glenn Jaffe, Ursula Schmidt-Erfurth, David Brown, Andre V. Gomes, James Warburton, Andreas Weichselberger, Frank G. Holz

Abstract

Objective
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 (AMD).

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

Patients
(N = 1817) with untreated, active choroidal neovascularization due to AMD 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 measure
The primary hypothesis was noninferiority in mean best corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key endpoints included percentage of patients who maintained q12w dosing through Week 48 and anatomical 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 in HAWK; +6.9 [brolucizumab 6 mg] vs +7.6 [aflibercept] letters in 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% in HAWK and 51% in HARRIER).

At Week 16, following identical treatment exposure, fewer brolucizumab 6 mg–treated eyes had disease activity vs 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 vs 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). Anatomical 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. Anatomical outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept. (ClinicalTrials.gov; NCT02307682, NCT02434328)