Glaucoma is the leading cause of irreversible blindness, impacting 80 million people worldwide. The only proven approach to prevent vision loss in glaucoma is the reduction of intraocular pressure (IOP), which is most commonly achieved by topical medications. Once daily (QD) prostaglandins are a typical first-line therapy, though the need for adjunctive therapy with other drug classes is very common. Several studies have suggested that the addition of brimonidine, an alpha-2 agonist, is the most effective for IOP lowering. Brimonidine is also preferred as a frontline therapy for normal tension glaucoma and patients undergoing laser trabeculoplasty or iridotomy, and has been shown to have potential neuroprotective benefits independent of IOP lowering. However, brimonidine is prescribed for three times daily (TID) dosing. The more drops glaucoma patients are required to take per day, the more likely it is that issues with adherence and symptoms of ocular surface disease develop. Thus, there is a significant opportunity to develop eye drops that can be used less frequently while also mitigating or even alleviating symptoms of concomitant dry eye disease. Novus Vision Inc. is developing a novel hypotonic thermosensitive gelling eye drop (OcuGel) that is liquid at room temperature and spreads to cover the ocular surface immediately and uniformly, forming a clear gel to trap the medication in place. Further, the gel coating provides sustained ocular surface lubrication and tear film stabilization to alleviate symptoms of dry eye. We have observed that when formulating our OcuGel vehicle containing brimonidine tartrate (OcuGel BT), OcuGel BT provided increased and more sustained IOP lowering compared to Alphagan P. To further enhance and sustain IOP lowering to achieve a QD product, here we aim to reformulate at the highest brimonidine concentration previously approved and marketed, 0.2%. Reformulation work in Aim 1 will involve creating formulations with pharmaceutically appropriate buffering and preservation for shelf stability and repeat use packaging, and to demonstrate stability under accelerated degradation conditions and sterility using industry standard tests. We will identify at least three formulations at in Aim 1 for pharmacodynamic evaluations and preclinical safety testing in rabbits in Aim 2. Using these data and our plan for IND-enabling studies in Aim 3, we will then engage in a pre-IND meeting with the FDA. Based on FDA feedback, we will contract to perform GLP bottle fills, stability and sterility and to perform GLP toxicity studies in rabbits and mini-pigs. Upon completion of Aim 3, we will have an appropriate data package for an IND submission.
Public Health Relevance Statement: PROJECT NARRATIVE Novus Vision Inc. is developing a novel eye drop drug delivery technology, OcuGel, that has promise for providing longer-lasting and more effective drug delivery to the anterior and posterior segments to treat a variety of ophthalmic diseases. Here, we describe preclinical development work to reformulate a brimonidine OcuGel eye drop as a pharmaceutically appropriate, shelf stable, repeat use formulation for once daily dosing to treat glaucoma. At the end of the project period, we will have an appropriate data package for an IND submission to continue development.
Project Terms: absorption; Acceleration; Acids; Award; Benzalkonium Chloride; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Borates; Buffers; High Pressure Liquid Chromatography; HPLC; High Performance Liquid Chromatography; High Speed Liquid Chromatography; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Dry Eye Syndromes; Dry eye disease; Keratoconjunctivitis Sicca; Eye; Eyeball; Eyedrops; Eye Drops; Feedback; Gel; Glaucoma; glaucomatous; Industry; Physiologic Intraocular Pressure; Intraocular Pressure; Ocular Tension; intra-ocular pressure; Lasers; Laser Electromagnetic; Laser Radiation; Light; Photoradiation; Lubrication; Marketing; Persons; Optics; optical; Legal patent; Patents; Patients; inorganic phosphate; Phosphates; Precipitation; precipitations; Prostaglandins; Prostanoids; Oryctolagus cuniculus; Domestic Rabbit; Rabbits; Rabbits Mammals; Recommendation; Safety; Miniature Swine; Minipigs; mini pig; mini-swine; miniswine; Tartrates; Technology; Temperature; Testing; Thinness; Leanness; Time; Tissues; Body Tissues; Trabeculectomy; Trabeculoplasty; Universities; Viscosity; Vision; Sight; visual function; Water; Hydrogen Oxide; Work; chlorine dioxide; Drug Delivery; Drug Delivery Systems; Film; sodium chlorite; density; Label; sterility testing; Anterior; Surface; Acute; Chronic; Evaluation; residential building; residential site; residence; Licensing; Measurement; fluid; liquid; Liquid substance; eye dryness; dry eye; Contracts; Contracting Opportunities; Area Under Curve; Hour; Frequencies; System; Blindness; vision loss; visual loss; Brimodine; brimonidine; bromoxidine; success; neuroprotection; neuroprotective; alpha 2 agonist; a2 agonist; Toxic effect; Toxicities; Sterility; sterile; novel; Pharmacodynamics; surface coating; Drops; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; preventing; prevent; Dose; Symptoms; Adherence; Aliquot; Data; International; Development; developmental; ocular surface; pre-clinical safety; preclinical safety; safety testing; stability testing; risk mitigation; phase II study; phase 2 study; Industry Standard; Formulation; systemic toxicity; alleviate symptom; ameliorating symptom; decrease symptom; fewer symptoms; relieves symptoms; symptom alleviation; symptom reduction; symptom relief; reduce symptoms; clinical development; pre-clinical development; preclinical development; preservation; retinal toxicity; eye toxicity; ocular toxicity; pre-Investigational New Drug meeting; Pre IND FDA meeting; Pre-IND mtg; pre-IND consultation; pre-IND discussion; pre-IND meeting; ocular surface disease; ocular surface disorder
