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Francesco Impagnatiello, Laura Storoni, Stefania Brambilla, Emanuela Masini, Cecilia Lanzi, Carol B Toris, Michael V.W. Bergamini, Ennio Ongini, Elena Bastia; Intraocular pressure-lowering and ocular exposure of NCX 1653, a novel nitric oxide-donating travoprost in models of ocular hypertension and glaucoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3034.
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© ARVO (1962-2015); The Authors (2016-present)
Nitric oxide (NO) and prostaglandin F2alpha (PGF2α) analogues lower intraocular pressure (IOP) by improving conventional and uveoscleral outflow, respectively. These mechanisms have been combined successfully into a new class of compounds, notably including latanoprostene bunod (LBN), an NO-donating derivative of latanoprost, in clinical development for the reduction of IOP in open-angle glaucoma and ocular hypertension. We describe NCX 1653, a novel NO-donating PGF2α analogues, with the NO-donating moiety linked to travoprost. Specifically, we studied the IOP-lowering activity of NCX 1653 in rabbits and non-human primates as well as ocular exposure in rabbits.
New Zealand white (NZW) rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits) and cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys) were used. In tOHT-rabbits, 0.1 ml of saline solution (5%) was injected into the vitreous humor of both eyes. IOP was measured prior to (baseline) and during the following 5 hours post-dosing of NCX 1653, equimolar travoprost or vehicle. In OHT-monkeys, various doses of NCX 1653 were compared to equimolar travoprost following PM or AM dosing. The levels of travoprost acid following administration of NCX 1653 or equimolar travoprost were determined in aqueous humor (AH) of NZW rabbits.
NCX 1653 (0.04%, 30μl) lowered IOP in tOHT rabbits with an Emax of -8.2±1.2 mmHg at 120 min. Travoprost at equimolar dose (0.03%, 30μl) showed minimal efficacy (Emax= -3.5±0.9 mmHg) in this model. In OHT-monkeys, NCX 1653 (0.04%, AM dosing) lowered IOP with an E300min of -6.7±1.6 mmHg compared to travoprost (0.03%, E300min of -4.9±2.3 mmHg). Furthermore, NCX 1653 effects were dose-dependent across 0.0052%, 0.04% and 0.13% PM dosing. Despite superior IOP-lowering activity, NCX 1653 (0.04%) treated eyes had lower travoprost acid levels compared to equimolar travoprost (0.18±0.09μM vs 0.34±0.05μM, respectively) in rabbit AH 60 min post-dosing.
NCX 1653 lowers IOP more than equimolar travoprost in tOHT-rabbits despite lower prostaglandin exposure in AH, consistent with previous data suggesting the preferential sensitivity of this model to NO. In OHT-monkeys, IOP-lowering effects of NCX 1653 are similar to those of travoprost. Additional compounds belonging to the same class are under investigation.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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