Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, California, USA.
Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, California, USA.
Am J Ophthalmol. 2022 Feb;234:223-234. doi: 10.1016/j.ajo.2021.11.002. Epub 2021 Nov 13.
No approved therapies directly target retinal ganglion cells (RGCs) for neuroprotection or neuroenhancement in glaucoma. Recombinant human nerve growth factor (rhNGF) has been shown to promote RGC survival and function in animal models of optic neuropathy. Here we evaluate the safety, tolerability, and efficacy of short-term, high-dose rhNGF eye drops versus placebo in a cohort of glaucoma patients.
This was a prospective, phase 1b, single-center, randomized, double-masked, vehicle-controlled, parallel-group study.
This study was designed to assess safety and tolerability as well as short-term neuroenhancement of structure and function (clinicaltrials.gov NCT02855450). A total of 60 open-angle glaucoma patients were randomized 40:20 to receive either 180 μg/mL rhNGF or vehicle control eye drops in both eyes, 3 times daily for 8 weeks, with a 24-week post-treatment follow-up. One eye was officially selected as the study eye, although both eyes were studied and dosed. Primary endpoints were safety, as assessed by adverse events, and tolerability, as assessed by patient-reported outcomes. Secondary outcome measures included best corrected visual acuity (BCVA), Humphrey visual field, electroretinograpy (ERG), and optical coherence tomography (OCT) of retinal nerve fiber layer (RNFL) thickness at baseline, after 8 weeks of treatment, and at 4 and 24 weeks after treatment (12 and 32 weeks total).
Of the 60 randomized patients, 23 were female (38%) and the average age was 66.1 years. Through week 32, there were no treatment-related serious adverse events, including no unexpectedly severe progression of optic neuropathy, no adverse events affecting ocular function or pressure, and no drug-related systemic toxicity. Topical high-dose rhNGF was tolerated well, with a low level of symptom burden mainly eliciting periocular ache (in 52% of treated group and 5% of placebo group) and only 3 patients (7.5%) discontinuing treatment because of discomfort, of whom 1 patient (2.5%) prematurely withdrew from the study. There were no statistically significant differences in global indices of Humphrey visual field and no meaningful differences in total, quadrant, or clock-hour mean RNFL thickness between the groups, although both of these function and structure measures showed nonsignificant trends toward significance in favor of rhNGF. Real-world participant data was used to generate an estimate of cohort size needed to power subsequent studies.
Use of rhNGF is safe and tolerable in a topical 180-μg/mL formulation. Although no statistically significant short-term neuroenhancement was detected in this trial, given the strong effects of NGF in preclinical models and the trends detected in this study, analysis for efficacy in a neuroprotection trial is warranted. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
没有经过批准的疗法可以直接针对神经节细胞（RGC）进行神经保护或神经增强治疗青光眼。重组人神经生长因子（rhNGF）已被证明可促进动物模型视神经病变中 RGC 的存活和功能。在这里，我们评估了短期高剂量 rhNGF 滴眼液与安慰剂在一组青光眼患者中的安全性、耐受性和疗效。
这是一项前瞻性、1b 期、单中心、随机、双盲、载体对照、平行组研究。
该研究旨在评估安全性和耐受性，以及结构和功能的短期神经增强（clinicaltrials.gov NCT02855450）。共有 60 名开角型青光眼患者随机分为 40:20 组，分别接受 180μg/ml rhNGF 或载体对照滴眼液，每日 3 次，共 8 周，治疗后 24 周随访。一只眼睛被正式选为研究眼，尽管两只眼睛都进行了研究和给药。主要终点是安全性，通过不良事件评估；以及耐受性，通过患者报告的结果评估。次要终点包括最佳矫正视力（BCVA）、Humphrey 视野、视网膜电图（ERG）和光学相干断层扫描（OCT）的视网膜神经纤维层（RNFL）厚度，分别在基线、治疗 8 周后和治疗后 4 周和 24 周（总共 12 周和 32 周）。
在 60 名随机患者中，有 23 名女性（38%），平均年龄为 66.1 岁。在第 32 周时，没有与治疗相关的严重不良事件，包括视神经病变无意外严重进展、无影响眼部功能或眼压的不良事件，以及无药物相关的全身毒性。局部高剂量 rhNGF 耐受性良好，症状负担水平较低，主要引起眶周疼痛（治疗组为 52%，安慰剂组为 5%），只有 3 名患者（7.5%）因不适而停止治疗，其中 1 名患者（2.5%）提前退出研究。两组的 Humphrey 视野的全球指数没有统计学上的显著差异，总、象限或时钟小时平均 RNFL 厚度也没有有意义的差异，尽管这两种功能和结构测量都显示出有利于 rhNGF 的无意义趋势。使用真实世界参与者的数据生成了估计后续研究所需的队列规模。
rhNGF 以局部 180μg/ml 制剂使用是安全和耐受的。尽管在这项试验中没有检测到统计学上显著的短期神经增强作用，但鉴于 NGF 在临床前模型中的强大作用以及本研究中检测到的趋势，有必要分析神经保护试验中的疗效。注意：本文的出版由美国眼科学会赞助。
