Phase 1b Randomized Controlled Study of Short Course Topical Recombinant Human Nerve Growth Factor (rhNGF) for Neuroenhancement in Glaucoma: Safety, Tolerability, and Efficacy Measure Outcomes

Abstract

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

Design: This was a prospective, phase 1b, single-center, randomized, double-masked, vehicle-controlled, parallel-group study.

Methods: 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).

Results: 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.

Conclusions: 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.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Study Visit Schedule. Multiple visits (Screening, Day 0, Week 8, Week 12, and Week 32) required patients to return two or three days in the same week for testing, including repeat visual fields.

Figure 2.

Study design and patient disposition. In sixty (60) open-angle glaucoma patients, one eye was officially selected as the study eye although both eyes underwent dosing and data collection. Primary endpoints were safety, as assessed through adverse events, and tolerability, as assessed through Visual Analogue Scale (VAS). Secondary objectives were to measure changes in best corrected visual acuity (BCVA), Humphrey visual field (HVF), electroretinography (ERG), and optical coherence tomography (OCT) at baseline and at the week 8, 12, and 32 visits. Exploratory objectives included flavoprotein fluorescence and adaptive optics imaging and OCT angio. Results through week 32 for all subjects are reported.

Figure 3.

Mean intraocular pressure (IOP) at baseline, treatment and follow-up periods in study eyes. Standard error of the mean (SEM) indicated by vertical bars. Note that follow-up time is not on a linear scale.

Figure 4.

Ocular tolerability by a visual analog scale (VAS) from 0 to 100 mm (0= “no symptoms”; 100= “worst possible discomfort”) for each of 7 different symptoms: foreign body sensation, burning or stinging, itching, ocular pain, sticky feeling, blurred vision, and photophobia. Percentage of patients by 10mm categories by study arm, by visit, plotted.

Figure 5.

Best-corrected distance visual acuity (BCVA) as ETDRS letters at baseline, treatment and follow-up periods in study eyes. Standard error of the mean (SEM) indicated by vertical bars. Note that follow-up time is not on a linear scale.

Figure 6.

Mean optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness at baseline, treatment and follow-up visits in study eyes. Standard deviation (SD) indicated by vertical bars. Note that follow-up time is not on a linear scale.

Figure 7.

Change in sectoral RNFL thickness by clock hour at (A) baseline to 8 weeks, and at (B) baseline to 32 weeks.

Figure 8.

Change in mean deviation (MD) of the visual fields by treatment arm and follow-up periods from baseline, in study eyes. Standard deviation (SD) indicated by vertical bars. Note that follow-up time is not on a linear scale.

Figure 9.

Required sample sizes for 80 percent power in t-test of retinal nerve fiber layer (RNFL). Curve for 80% power and significance level 0.05 for a t-test between two groups assuming that the within-group variability in changes is completely due to measurement error that has standard deviation (SD) 4.0.