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Ophthalmology. 2019 Apr 12. pii: S0161-6420(18)33018-5. doi: 10.1016/j.ophtha.2019.04.017. [Epub ahead of print]

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

Author information

1
Retinal Consultants of Arizona, Phoenix, Arizona; University of Southern California, Los Angeles, California. Electronic address: pdugel@gmail.com.
2
Eye & Retina Surgeons, Singapore.
3
Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
4
Duke Eye Center, Durham, North Carolina.
5
Medical University of Vienna, Vienna, Austria.
6
Retina Consultants of Houston, Houston, Texas.
7
University of Sao Paulo, Sao Paulo, Brazil.
8
Novartis Pharma AG, Basel, Switzerland.
9
University of Bonn, Bonn, Germany.

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).

PMID:
30986442
DOI:
10.1016/j.ophtha.2019.04.017
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