GS-101 Antisense Oligonucleotide Eye Drops Inhibit Corneal Neovascularization Interim Results of a Randomized Phase II Trial
GS-101 Antisense Oligonucleotide Eye Drops Inhibit Corneal Neovascularization Interim Results of a Randomized Phase II Trial
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DOI：
10.1016/j.ophtha.2009.04.016
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发表时间：
2009-09-01
期刊：
影响因子：
13.7
通讯作者：
Meller, Daniel
中科院分区：
文献类型：
--
作者：
Cursiefen, Claus;Bock, Felix;Meller, Daniel
目的：病理性角膜新生血管不仅降低了角膜透明度和视力，而且是角膜移植术后移植物排斥反应的最重要的术前和术后危险因素之一。本研究的目的是测试基因信号（GS）-101滴眼液（一种针对胰岛素受体底物-1的反义寡核苷酸）与安慰剂相比抑制进行性角膜新生血管形成的耐受性和功效。设计：随机、双盲、多中心、II期临床研究。对40例进行性角膜新生血管患者进行中期分析，这些患者是由于各种基础疾病对常规治疗无反应所致。在这项剂量探索研究中，对4组10名患者进行了为期3个月的治疗，比较了3种剂量的GS-101（每日两次滴眼液;总计43、86和172 μ g/天）与安慰剂（每组10名患者）。主要终点是病理性角膜血管覆盖的面积，使用图像分析技术在数字化裂隙灯图片上进行形态测量。结果：GS-101滴眼液耐受性良好。研究者将所有严重不良事件和95%的所有其他不良事件归类为不相关。在3例患者中，存在眼表不适的潜在相关副作用。剂量为86 μ g/天（43 μ g/滴），GS-101滴眼液对角膜新生血管产生显著的抑制和消退作用（角膜总面积的-2.04 +/-1.57%; P = 0.0047），而低剂量趋于稳定（0.07 +/- 2.94%; P = 0.2088）与安慰剂组（0.89 +/- 2.15%）相比，所有患者的角膜新生血管均进展。有没有明显的好处，以较高的剂量（1.60 +/- 7.63%）。结论：本II期研究的中期结果表明，GS-101滴眼液在86 μ g/天的最佳剂量是一种有效的和非侵入性的方法，特别是抑制和消退活跃的角膜血管生成，角膜移植和移植排斥反应的主要危险因素。未检测到安全性问题。
Purpose: Pathologic corneal neovascularization not only reduces corneal transparency and visual acuity, but also is one of the most significant preoperative and postoperative risk factors for graft rejection after corneal transplantation. The aim of this study was to test tolerability and efficacy of gene signal (GS)-101 eye drops, an antisense oligonucleotide against insulin receptor substrate-1, versus placebo on inhibition of progressive corneal neovascularization.Design: Randomized, double-blind, multicenter, phase II clinical study.Participants and Controls: Interim analysis on 40 patients with progressive corneal neovascularization resulting from various underlying diseases being nonresponsive to conventional therapy.Interventions: Four groups of 10 patients were treated for 3 months in this dose-finding study comparing 3 doses of GS-101 (eye drops twice daily; 43, 86, and 172 mu g/day total) with placebo (10 patients per group).Main Outcome Measures: The primary end point was the area covered by pathologic corneal blood vessels, which was measured morphometrically on digitized slit-lamp pictures using image analysis techniques.Results: GS-101 eye drops were well tolerated. All serious and 95% of all other adverse events were categorized by the investigators as unrelated. In 3 patients, there was a potentially related side effect of ocular surface discomfort. At a dose of 86 mu g/day (43 mu g/drop), GS-101 eye drops produced a significant inhibition and regression of corneal neovascularization (-2.04 +/- 1.57% of total corneal area; P = 0.0047), whereas the low dose tended to stabilize it (0.07 +/- 2.94%; P = 0.2088) compared with placebo (0.89 +/- 2.15%), where corneal neovascularization progressed in all patients. There was no apparent benefit to the higher dose (1.60 +/- 7.63%).Conclusions: The interim results of this phase II study suggest that GS-101 eye drops at an optimal dose of 86 mu g/day are an effective and noninvasive approach specifically to inhibit and regress active corneal angiogenesis, a major risk factor for corneal graft transplantation and graft rejection. Safety concerns were not detected.