Cole Eye Institute, Cleveland Clinic, Ohio, USA.
Am J Ophthalmol. 2010 Jul;150(1):33-39.e2. doi: 10.1016/j.ajo.2010.02.006.
To assess the safety, tolerability, pharmacokinetics, and dose-limiting toxicity of single intravitreal injection of Sirna-027, a small interfering RNA targeting vascular endothelial growth factor receptor-1, in patients with choroidal neovascularization (CNV) resulting from neovascular age-related macular degeneration (AMD). Secondary objectives included assessment of anatomic changes in retinal thickness, size of CNV, and changes in visual acuity.
Prospective, open-label, single-dose, dose-escalation phase 1 study.
Twenty-six eyes of 26 patients with a median age of 82 years and CNV resulting from AMD who had previous treatments with other therapies were treated at 2 academic retinal practices. Patients received a single dose of Sirna-027 (100, 200, 400, 800, 1200, or 1600 microg/eye). Blood was sampled for pharmacokinetic analysis at 1, 4, and 24 hours after injection and on day 7. Patients underwent ophthalmic examinations including visual acuity, fluorescein angiography, and optical coherence tomography at screening and days 7, 14, 28, and 84. The main outcome measures were adverse reactions and dose-limiting toxicities.
Intravitreal injection of a single dose of Sirna-027 from 100 to 1600 microg was well tolerated in patients with AMD, with no dose-limiting toxicity found. Adverse events were mild to moderate in severity. Adjusted mean foveal thickness decreased within 2 weeks after study treatment. The decrease was most pronounced in the 100- and 200-microg doses.
A single intravitreal dose of Sirna-027 up to 1600 microg/eye was well tolerated in patients with CNV resulting from neovascular AMD that had been refractory to other therapies. Stabilization or improvement in visual acuity and foveal thickness was observed. No dose-response or dose-limiting effects were noted.
评估靶向血管内皮生长因子受体-1 的小干扰 RNA （Sirna-027）玻璃体腔内单次注射治疗新生血管性年龄相关性黄斑变性（AMD）所致脉络膜新生血管（CNV）的安全性、耐受性、药代动力学和剂量限制性毒性。次要目标包括评估视网膜厚度、CNV 大小的解剖学变化以及视力变化。
前瞻性、开放性标签、单次剂量、剂量递增 1 期研究。
2 家学术视网膜诊所共纳入 26 例 26 只眼患者，中位年龄 82 岁，均患有曾接受过其他疗法治疗的 AMD 相关 CNV。患者接受 Sirna-027（100、200、400、800、1200 或 1600μg/眼）单次剂量治疗。注射后 1、4 和 24 小时以及第 7 天采血进行药代动力学分析。患者在筛选期和第 7、14、28 和 84 天接受眼科检查，包括视力、荧光素血管造影和光学相干断层扫描。主要观察指标为不良反应和剂量限制性毒性。
AMD 患者玻璃体腔内单次注射 Sirna-027 剂量从 100 至 1600μg 耐受良好，未发现剂量限制性毒性。不良反应的严重程度为轻度至中度。研究治疗后 2 周内，平均中心凹视网膜厚度降低，在 100μg 和 200μg 剂量时降低最明显。
在对其他疗法有抵抗的新生血管性 AMD 所致 CNV 患者中，单次玻璃体腔内注射 Sirna-027 高达 1600μg/眼可耐受良好。观察到视力和中心凹厚度的稳定或改善。未观察到剂量反应或剂量限制性作用。
