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.

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.

Comparison of 1-Year Effectiveness of Trabecular Microbypass Stent implantation (iStent) in Conjunction With Phacoemulsification Among Mild, Moderate, and Severe Primary Open-angle Glaucoma Patients.

PRECIS: The study compared 1-year effectiveness of single trabecular microbypass stent (iStent) implantation with phacoemulsification among glaucoma severities in primary open-angle glaucoma. The study found that mild glaucoma had greater success rate and lower number of medications compared with moderate and severe glaucoma. PURPOSE: To evaluate the effectiveness of iStent implantation in combination with cataract surgery in moderate to severe glaucoma compared with mild glaucoma. METHODS: Medical charts of primary open-angle glaucoma subjects undergoing 1 iStent implantation were retrospectively reviewed. Glaucoma was classified on the basis of mean deviation (MD) of the preoperative standard automated perimetry into mild (MD>-6 dB), moderate (MD -6 to -12 dB), and severe (MD<-12 dB). Mixed effect regression models were performed to determine the effect of iStent at 1 year. The outcomes included as follows: (1) intraocular pressure (IOP) and the number of medications, (2) eyes with IOP ≤ severity-based target (18 mm Hg for mild, 15 mm Hg for moderate, 12 mm Hg for severe) (2A) without medication, and (2B) with medication reduction. RESULTS: In total, 104 eyes from 89 subjects were analyzed. Cataract combined with iStent surgery significantly lowered the number of medications in all groups and significantly decreased IOP in moderate and severe glaucoma (P<0.05). There was significantly higher number of medications in moderate (ß: 0.58, P=0.002) and severe (ß: 1.20, P<0.001) compared with mild glaucoma. Eyes with moderate glaucoma had significantly lower rate of success (criterion 2A) compared with mild glaucoma [odds ratio (OR): 0.008, P=0.047]. Eyes with moderate and severe glaucoma had significantly lower rates of success (criterion 2B) (moderate vs. mild OR: 0.002, P=0.028; severe vs. mild OR: 0.026, P=0.026). CONCLUSIONS: Combined phacoemulsification with iStent seems to have a better IOP-lowering and medication-lowering effect in mild glaucoma cases versus those with moderate and severe glaucoma. This difference was found in real-world data over one-year follow-up period. Long-term studies with defined IOP goals and medication removal protocols are warranted.

Comparison of Using One Trabecular Microbypass Stent versus Two during Cataract Surgery at Two Sites: One-Year Follow-Up.

PURPOSE: To compare IOP and ocular hypotensive medication reduction of using one trabecular microbypass stent versus two in patients with open-angle glaucoma. Setting. Palo Alto Veterans Affairs (VA) Hospital and the Byers Eye Institute at Stanford University, Palo Alto, California, USA. DESIGN: Retrospective case series. METHODS: A chart review included patients who underwent trabecular microbypass implantation with cataract surgery in 2015-2017, with at least one-year follow-up. Subjects were divided into two groups by location (always one stent at Stanford versus two stents at the VA). Primary outcome measures included IOP and medication reduction at baseline and 12-month follow-up. RESULTS: 132 subjects (166 eyes) were included. The preoperative IOP was 16.3 ± 3.4 mmHg on 2.6 ± 1.1 medications in the one-stent group (N = 85) and 17.5 ± 3.1 mmHg on 2.7 ± 0.6 medications in the two-stent group (N = 81). There was no significant difference between the two groups (p = 0.06). At the 12-month visit, there was a 13.37% ± 2.93 reduction in IOP in the 1-stent group (p ≤ 0.001) and 13.49% ± 2.69 in the 2-stent group (p ≤ 0.001); both were not significantly different from each other (p = 0.074). At 12 months, there was also a 14.5% reduction in medication use for the 1-stent group and 15.3% reduction in the 2-stent group, both statistically significant from baseline, (p = 0.022 and p = 0.037, respectively). CONCLUSIONS: Implantation with either one or two stents during cataract surgery in patients with glaucoma demonstrated similar IOP and med reduction in both groups between the two sites.