Retinal Consultants of Arizona, Phoenix, Arizona; University of Southern California, Los Angeles, California.
Eye & Retina Surgeons, Singapore.
Ophthalmology. 2020 Jan;127(1):72-84. doi: 10.1016/j.ophtha.2019.04.017. Epub 2019 Apr 12.
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).
Double-masked, multicenter, active-controlled, randomized trials.
Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye.
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.
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.
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.
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).
两项设计相似的 3 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）。
双盲、多中心、活性对照、随机试验。
研究眼中未经治疗、有活动性脉络膜新生血管形成的未治疗、活跃的年龄相关性黄斑变性患者（N=1817）。
患者随机接受玻璃体腔内 brolucizumab 3 mg（仅 HAWK）或 6 mg 或 aflibercept 2 mg。在 3 个月的负荷剂量后，brolucizumab 治疗组每 12 周（q12w）注射一次，如果疾病活动存在，则间隔调整为每 8 周（q8w）；aflibercept 治疗组每 8 周给药一次。
主要假设是从基线到第 48 周时 brolucizumab 治疗的平均最佳矫正视力（BCVA）变化与 aflibercept 相比不劣（边际：4 个字母）。其他关键终点包括在第 48 周时通过 q12w 剂量维持治疗的患者比例以及解剖学结果。
在第 48 周，每个 brolucizumab 组在 BCVA 从基线的变化方面均表现出与 aflibercept 的非劣效性（最小二乘[LS]均值，brolucizumab 6 mg 和 3 mg 组分别为+6.6[6 mg]和+6.1[3 mg]个字母，与 aflibercept 的+6.8 个字母相比；HAWK 中的 brolucizumab 6 mg 与 aflibercept 的+6.9 个字母与+7.6 个字母相比；HARRIER；P<0.001）。超过 50%的 brolucizumab 6 mg 治疗组在第 48 周时维持 q12w 剂量（HAWK 中为 56%，HARRIER 中为 51%）。在第 16 周，在相同的治疗暴露后，与 aflibercept 相比，brolucizumab 6 mg 治疗组的疾病活动较少（HAWK 中为 24.0%，HARRIER 中为 32.2%；P=0.001）。与 aflibercept 相比，brolucizumab 6 mg 在第 48 周时从基线到第 48 周时中央视网膜下厚度的减少更为明显（LS 均值-172.8μm 与-143.7μm；P=0.001）和 HARRIER（LS 均值-193.8μm 与-143.9μm；P<0.001）。解剖学视网膜液结果有利于 brolucizumab 优于 aflibercept。总体而言，brolucizumab 和 aflibercept 的不良反应发生率大致相似。
在第 48 周时，brolucizumab 在视觉功能方面与 aflibercept 非劣效，超过 50%的 brolucizumab 6 mg 治疗组在第 48 周时维持 q12w 剂量间隔。解剖学结果有利于 brolucizumab 优于 aflibercept。总体而言，brolucizumab 的安全性与 aflibercept 相似（ClinicalTrials.gov；NCT02307682，NCT02434328）。
