Safety and Pharmacokinetics of Escalating Doses of Human Recombinant Nerve Growth Factor Eye Drops in a Double-Masked, Randomized Clinical Trial

Abstract

Background and ObjectivesNerve growth factor (NGF) is a neurotrophin with therapeutic possibilities that extend from the nervous system to the eye. We tested the safety, maximal tolerated dose, pharmacokinetics, and antigenicity of a novel human recombinant NGF (rhNGF) eye-drop formulation in a phase I study.MethodsThis prospective, randomized, double-masked, vehicle-controlled trial, sponsored by Dompé SpA (registered as NCT01744704 at ClinicalTrials.gov), enrolled 74 healthy volunteers (24 females, 50 males, age 40.2 ± 11.8 years). Subjects were randomized in three cohorts to receive (1) a single eye-drop containing 0.0175, 0.175, or 0.7 μg rhNGF; (2) a single ascending dose of rhNGF eye drops three times a day for 1 day (total daily dose 2.1, 6.3, or 18.9 μg), or vehicle; or (3) a multiple ascending dose of rhNGF eye drops three times a day for 5 days (total dose 10.5, 31.5, or 94.5 μg), or vehicle. Outcome measures included blood chemistry, urinalyses, vital signs, electrocardiograms (ECGs), serum NGF antibodies, ocular and systemic adverse events (AEs), visual acuity, tear function, intraocular pressure, fundus oculi, and ocular symptoms.ResultsAdministration of rhNGF eye drops did not result in a significant increase of circulating NGF levels and no antidrug antibodies were detected in serum. No serious AEs were recorded, and a few mild, transient ocular AEs related to rhNGF administration were reported only at the highest concentration.ConclusionsrhNGF eye drops were well tolerated, with no detectable clinical evidence of systemic AEs. These results pave the way for the development of clinical trials on rhNGF in ophthalmology.

Role of corneal nerves in ocular surface homeostasis and disease

“…More recently, a recombinant human NGF eye drop formulation was developed and demonstrated good safety and tolerability in phase I (Ferrari et al. ). Thereafter, the formulation underwent clinical evaluation (Mantelli et al.…”

Pharmacological approaches to retinitis pigmentosa: A laboratory perspective

“…A secondary objective of the clinical trial is to test the potential efficacy of rhNGF in slowing the deterioration of visual function in RP (ClinicalTrials.gov Identifier: NCT02110225). Recent reports from the clinical trial group show that the administration of rhNGF eye drops does not result in any systemic or ocular adverse effect, with a general good tolerability of the medication (Ferrari et al, 2014). Hopefully future data of this the study will disclose the possibility of a neuroprotective action on the human RP retina.…”

“…An ongoing clinical trial aims at assessing the safety and tolerability of human NGF administered as an eye drops solution to patients with typical RP, compared to matched controls administered with vehicle alone (Ferrari et al, 2014). In this study, the recombinant form, rhNGF, has replaced the original molecule.…”

Nerve Growth Factor Modulation of Retinal Ganglion Cell Physiology

“…Thanks to the recent introduction of a recombinant human NGF as an eye drop formulation, that has already been proven safe in Phase-I clinical trials (Ferrari et al, 2013), wide randomized controlled Phase-II clinical trials have already been planned to investigate the use of NGF in widespread ocular neurodegenerative diseases, like glaucoma.…”