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).

中文翻译：

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HAWK和HARRIER：Brolucizumab用于新血管性年龄相关性黄斑变性的3期多中心，随机，双层屏蔽试验。

目的两项类似设计的3期临床试验（HAWK和HARRIER）比较了溴珠单抗（一种抑制血管内皮生长因子A的单链抗体片段）与阿柏西普治疗新血管性年龄相关性黄斑变性（nAMD）的比较。设计双掩蔽，多中心，主动控制的随机试验。参与者（N = 1817）由于年龄相关的黄斑变性而导致未经治疗的活动性脉络膜新血管形成患者。干预将患者随机分为3毫克（仅HAWK），6毫克或阿柏西普2毫克。每月3次注射负荷后，经布洛珠单抗治疗的眼睛每12周（q12w）接受一次注射，如果存在疾病活动，则将间隔调整为每8周（q8w）。使用阿柏西普治疗的眼睛接受q8w剂量。主要观察指标主要假设是从基线到第48周的平均最佳矫正视敏度（BCVA）变化为非劣效（间隔：4个字母）。其他关键终点包括在第48周内维持q12w剂量的患者百分比以及解剖结局。结果在第48周，每个溴珠单抗臂均显示出abribercept对BCVA的非劣效性相对于基线的变化（溴平方单抗的最小二乘[LS]平均值，+ 6.6 [6 mg]和+6.1 [3 mg]字母，与aflibercept [HAWK]的+6.8字母]； + 6.9 [brolucizumab 6 mg]与+7.6 [aflibercept]字母[HARRIER]；每次比较P <0.001）。到第48周，在q12w剂量下，接受大于50％的布洛珠单抗6 mg治疗的眼睛保持不变（56％[HAWK]和51％[HARRIER]）。在第16周，经过相同的治疗后，在HAWK（24.0％vs. 34.5％; P = 0.001）和HARRIER（22.7％vs. 32.2％; P = 0.002）中，用6 mg溴珠单抗治疗的眼睛的疾病活动性优于aflibercept。在HAWK（LS平均-172.8μmvs. -143.7μm； P = 0.001）和HARRIER（LS平均-193.8μm与-143.9μm； HAWK（LS平均-172.8μmvs. -143.9μm）中，使用溴珠单抗6 mg与aflibercept相比，从基线到第48周观察到更大的中心子场厚度减少。 P <0.001）。解剖性视网膜液转归优于溴单抗，而不是阿柏西普。总体而言，溴西珠单抗和阿柏西普的不良事件发生率通常相似。结论在第48周，布洛珠单抗在视觉功能上不逊于abribercept，并且在第48周的第12周用药间隔内，维持50％以上的经blucizumab 6 mg治疗的眼睛。解剖学结局优于abribercept。