Supplementary Material for: Relationship between Aflibercept Efficacy and Genetic Variants of Genes Associated with Neovascular Age-Related Macular Degeneration: The BIOIMAGE Trial

Purpose: To identify the genetic variants of the vascular endothelial growth factor (VEGF) pathway genes and other genes associated with neovascular age-related macular degeneration (nAMD) as possible predictive biomarkers of a favorable treatment response to aflibercept. Design: A 52-week (with extension phase: 104-week), prospective, open-label, single-arm, multicenter, phase IV trial was conducted in Spain. Participants: Patients with nAMD were enrolled. Methods: Aflibercept was administered every 8 weeks until week 48 (after 1-monthly loading doses over 3 months). After week 48, the interval between visits for aflibercept administration was extended by 2 weeks per visit to a maximum of 12 weeks if no evidence of disease activity was observed. A total of 338 SNPs in 90 genes associated with nAMD were analyzed. Main Outcome Measures: Efficacy was evaluated mainly with best-corrected visual acuity (BCVA), and adverse events (AEs) were reported. Treatment efficacy was defined as an increase in BCVA ≥15 letters versus the baseline visit. Univariate and multivariate logistic regressions were used to associate single-nucleotide polymorphisms (SNPs) and treatment efficacy. Results: 194 nonconsecutive patients were enrolled, 170 completed the 52-week follow-up, and of the 85 patients who started the extension phase, 77 completed this phase. Mean BCVA increased from baseline to weeks 52 and 104 by 9 and 10 letters (p = 0.0001 for both), respectively. The percentages of patients gaining ≥15 letters in weeks 52 and 104 were 33 and 31%, respectively. Multivariate logistic regression showed significant associations of 6 SNPs (in 6 genes) with treatment efficacy: rs12366035 (VEGFB; TT; odds ratio [OR] 217), rs25681 (C5; AA/AG; OR 19.7/8.3), rs17793056 (CX3CR1; CT/CC; OR 8.1/6.2), rs1800775 (CETP; CC; OR 6.6), rs2069845 (IL6; GG/AA; OR 5.6/3.3), and rs13900 (CCL2; CT; OR 4.0). One percent of the patients reported arteriothrombolic events related to aflibercept (cerebrovascular accident) according to the Antiplatelet Trialist Collaboration, and 2% reported serious ocular (retinal pigment epithelial tear, retinal tear, and endophthalmitis) and systemic (cardiac failure, hypersensitivity, and transient ischemic attack) AEs related to aflibercept. Conclusions: Results suggest strong pharmacogenetic associations between one genetic variant of VEGFB (TT, rs12366035) and C5 (AA, rs12366035) genes and the BCVA response after 52-week aflibercept treatment in patients with nAMD. Likewise, the results support the efficacy of aflibercept observed in phase III studies and a good safety profile.

研究目的：旨在识别血管内皮生长因子（vascular endothelial growth factor, VEGF）通路基因及其他与新生血管性年龄相关性黄斑变性（neovascular age-related macular degeneration, nAMD）相关的基因的遗传变异，将其作为阿柏西普（aflibercept）治疗应答良好的潜在预测生物标志物。试验设计：本研究为一项在西班牙开展的为期52周（延长期为104周）的前瞻性、开放标签、单臂多中心IV期临床试验。研究对象：纳入新生血管性年龄相关性黄斑变性患者。研究方法：阿柏西普给药方案为：前3个月每月给予负荷剂量，之后每8周给药一次，直至第48周。第48周后，若未观察到疾病活动证据，则每次随访将给药间隔延长2周，最长至12周。本研究对90个与nAMD相关的基因中的338个单核苷酸多态性（single-nucleotide polymorphisms, SNPs）进行了分析。主要结局指标：疗效主要通过最佳矫正视力（best-corrected visual acuity, BCVA）进行评估，不良事件（adverse events, AEs）则予以记录。治疗疗效定义为相较于基线访视，最佳矫正视力提升≥15个字母。采用单变量及多变量logistic回归分析，以关联单核苷酸多态性与治疗疗效。研究结果：共纳入194例非连续性患者，其中170例完成了52周随访；启动延长期的85例患者中，77例完成了该阶段随访。从基线至第52周及第104周，患者平均最佳矫正视力分别提升了9个和10个字母（两者P值均为0.0001）。第52周及第104周时，视力提升≥15个字母的患者占比分别为33%和31%。多变量logistic回归分析显示，6个基因中的6个单核苷酸多态性与治疗疗效存在显著关联：rs12366035（VEGFB；TT；比值比[odds ratio, OR] 217）、rs25681（C5；AA/AG；比值比[OR] 19.7/8.3）、rs17793056（CX3CR1；CT/CC；比值比[OR] 8.1/6.2）、rs1800775（CETP；CC；比值比[OR] 6.6）、rs2069845（IL6；GG/AA；比值比[OR] 5.6/3.3）以及rs13900（CCL2；CT；比值比[OR] 4.0）。根据抗血小板试验协作组（Antiplatelet Trialist Collaboration）的标准，1%的患者报告了与阿柏西普相关的动脉血栓事件（脑血管意外）；2%的患者报告了与阿柏西普相关的严重眼部不良事件（视网膜色素上皮撕裂、视网膜撕裂及眼内炎）与全身不良事件（心力衰竭、超敏反应及短暂性脑缺血发作）。研究结论：本研究结果表明，VEGFB基因的一种遗传变异（TT基因型，rs12366035）与C5基因的遗传变异（AA基因型，rs12366035）存在较强的药物基因组学关联，与新生血管性年龄相关性黄斑变性患者接受52周阿柏西普治疗后的最佳矫正视力应答相关。此外，本研究结果验证了III期临床试验中观察到的阿柏西普疗效，并证实其良好的安全性特征。