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Francesco Impagnatiello, Elena Bastia, Carol B Toris, Achim H Krauss, Ganesh Prasanna, Ennio Ongini; NCX 470, a nitric oxide (NO)-donating bimatoprost lowers intraocular pressure in rabbits, dogs and non-human primate models of glaucoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5809.
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Bimatoprost (Lumigan®) is among the most clinically effective intraocular pressure (IOP) lowering drugs on the market. However, bimatoprost elicits more eye irritation than other prostaglandin PGF2α analogues in clinical use. Approaches aimed at retaining equal or superior IOP-lowering efficacy while reducing the side-effects of bimatoprost are of potential clinical interest. A dual mechanism-of-action compound involving nitric oxide (NO) donation and PGF2α agonist activity has recently shown IOP lowering efficacy in phase 3 clinical studies. We report the pharmacological profile of NCX 470, a novel proprietary NO-donating bimatoprost in advanced preclinical development, in rabbit, dog and non-human primate models of glaucoma.
New Zealand white rabbits were injected with 0.1 ml of hypertonic saline solution (5%) into the vitreous humor of both eyes. NCX 470 or vehicle was instilled immediately after the injection of hypertonic saline. IOP was determined prior to (baseline) hypertonic saline and for 5 hours post dosing. IOP-lowering effects (12 and 18 hours post-dosing) of NCX 470 were studied in normotensive dogs and female cynomolgus monkeys with unilateral laser-induced ocular hypertension. Equimolar doses of bimatoprost (0.1% and 0.03% in rabbits and dogs or non-human primates, respectively) were used as the comparator in all studies.
NCX 470 (0.1%) significantly lowered IOP in ocular hypertensive rabbits with a reduction vs. vehicle of -3.9±2.5, -5.6±2.8 and -5.3±1.5 mmHg at 60, 90 and 180 min, respectively. Bimatoprost alone was not effective in the rabbit model. Topical NCX 470 (0.04%) was more effective than equimolar (0.03%) bimatoprost in normotensive dogs (D vs. basal, -5.8±0.8 and -4.3±0.7 mmHg, respectively) and in ocular hypertensive non-human primates (D vs. basal, -7.7±1.2 and -4.8±1.6 mmHg, respectively) at 18 hours post dosing. Moreover, the IOP-lowering effects of NCX 470 in normotensive dogs were dose-dependent between 0.014% and 0.065%. The compound was well tolerated in all species.
Topical NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of ocular hypertension. These results suggest that NCX 470 warrants clinical evaluation for IOP-lowering equal or greater than bimatoprost with equivalent or reduced hyperemia.
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