HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration
HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration
复制标题
DOI：
10.1016/j.ophtha.2019.04.017
复制
发表时间：
2020-01-01
期刊：
影响因子：
13.7
通讯作者：
Holz, Frank G.
中科院分区：
文献类型：
--
作者：
Dugel, Pravin U.;Koh, Adrian;Holz, Frank G.
目的：两项设计相似的III期试验（HAWK和HARRIER）比较了brolucizumab（一种抑制血管内皮生长因子-A的单链抗体片段）与aflibercept治疗新生血管性年龄相关性黄斑变性（nAMD）的效果。设计：双盲、多中心、活性对照、随机试验。患者（N = 1817）在研究眼中患有由于年龄相关性黄斑变性引起的未经治疗的活动性脉络膜新生血管。患者随机接受玻璃体内注射3 mg（仅HAWK）或6 mg或aflibercept 2 mg。3个月注射负荷后，brolucizumab治疗的眼睛接受注射，每12周（q12 w）和间隔调整为每8周（q8 w），如果疾病活动存在; aflibercept治疗的眼睛接受q8 w dosage.Main结果测量：主要假设是平均最佳矫正视力（BCVA）从基线到第48周的变化的非劣效性（边缘：4个字母）。其他关键终点包括维持q12 w给药至第48周的患者百分比和解剖学结局。结果：在第48周，每个brolucizumab组在BCVA较基线变化方面均表现出非劣效于aflibercept（最小二乘[LS]平均值，brolucizumab组为+6.6 [6 mg]和+6.1 [3 mg]字母，aflibercept组为+6.8字母[HAWK];+6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept]字母[HARRIER];每次比较P < 0.001）。超过50%的brolucizumab 6 mg治疗眼维持q12 w给药直至第48周（56% [HAWK]和51%[HARRIER]）。第16周时，在相同的治疗暴露后，与阿柏西普相比，HAWK（24.0% vs. 34.5%; P = 0.001）和HARRIER（22.7% vs. 32.2%; P = 0.002）中接受brolucizumab 6 mg治疗的患眼具有更少的疾病活动性。在HAWK（LS均值-172.8 mu m vs. -143.7 mu m; P = 0.001）和HARRIER（LS均值-193.8 mu m vs.-143.9 mu m; P < 0.001）中，与阿柏西普相比，在brolucizumab 6 mg组中观察到中心亚区厚度从基线至第48周的降低幅度更大。解剖学视网膜液结局支持brolucizumab优于aflibercept。总体而言，不良事件发生率与brolucizumab和aflibercept.Conclusions大致相似：Brolucizumab在第48周的视觉功能方面不劣于aflibercept，并且>50%的brolucizumab 6 mg治疗的眼睛维持q12 w给药间隔至第48周。解剖学结局支持brolucizumab优于aflibercept。brolucizumab的总体安全性与美国眼科学会的aflibercept（C）2019相似。
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 mu m vs. -143.7 mu m; P = 0.001) and HARRIER (LS mean -193.8 mu m vs. -143.9 mu m; 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 (C) 2019 by the American Academy of Ophthalmology.