Purpose

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 safety, tolerability, and efficacy of short-term, high-dose rhNGF eye drops versus placebo in a cohort of glaucoma patients.

Methods

This study is a single-center, randomized, double-masked, vehicle-controlled, parallel group study designed to assess safety and tolerability as well as short-term neuroenhancement of structure and function (Clinicaltrials.gov NCT02855450). Sixty open-angle glaucoma patients were randomized 40:20 to receive either 180 μg/ml rhNGF or vehicle control eye drops in both eyes, three 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 through adverse events, and tolerability, as assessed through patient reported outcomes. Secondary outcome measures included best corrected visual acuity (BCVA), Humphrey visual field (HVF), electroretinogram (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).

Results

Of the 60 randomized subjects, 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 low level of symptom burden mainly eliciting periocular ache (in 52% of treated, 5% of placebo) and only 3 patients (7.5%) discontinuing treatment due to discomfort, out of whom 1 patient (2.5%) prematurely withdrawing from the study. There were no statistically significant differences in global indices of HVF, 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 non-significant trends towards significance in favor of rhNGF. Real-world participant data was used to generate an estimate of cohort size needed to power subsequent studies.

Conclusions

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 trends detected in this study, analysis for efficacy in a neuroprotection trial is warranted.

中文翻译：

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用于青光眼神经增强的短期局部重组人神经生长因子 (rhNGF) 的 1b 期随机对照研究：安全性、耐受性和有效性测量结果

目的

没有批准的疗法直接针对视网膜神经节细胞 (RGC) 用于青光眼的神经保护或神经增强。重组人神经生长因子 (rhNGF) 已被证明可促进视神经病变动物模型中的 RGC 存活和功能。在这里，我们在一组青光眼患者中评估短期、高剂量 rhNGF 滴眼液与安慰剂相比的安全性、耐受性和有效性。

方法

本研究是一项单中心、随机、双盲、车辆对照、平行组研究，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）。60 名开角型青光眼患者以 40:20 的时间随机接受双眼接受 180 μg/ml rhNGF 或载体对照滴眼液，每天 3 次，持续 8 周，治疗后随访 24 周。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。主要终点是通过不良事件评估的安全性和通过患者报告的结果评估的耐受性。次要结果测量包括最佳矫正视力 (BCVA)、汉弗莱视野 (HVF)、视网膜电图 (ERG)、

结果

在 60 名随机受试者中，23 名女性（38%），平均年龄为 66.1 岁。到第 32 周，没有与治疗相关的严重不良事件，包括没有意外严重的视神经病变进展，没有影响眼功能或压力的不良事件，也没有与药物相关的全身毒性。局部大剂量 rhNGF 耐受性良好，症状负担低，主要引起眼周疼痛（治疗组 52%，安慰剂组 5%），仅有 3 名患者（7.5%）因不适而停止治疗，其中 1 名患者(2.5%) 过早退出研究。HVF 的全球指数没有统计学上的显着差异，各组之间的总、象限或时钟小时平均 RNFL 厚度没有显着差异，尽管这些功能和结构测量都显示出有利于 rhNGF 的非显着趋势。真实世界的参与者数据被用来估计为后续研究提供动力所需的队列规模。

结论

rhNGF 在局部 180 μg/ml 制剂中是安全且可耐受的。尽管在本试验中未检测到具有统计学意义的短期神经增强，但鉴于 NGF 在临床前模型中的强烈影响和本研究中检测到的趋势，有必要对神经保护试验中的功效进行分析。