June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Intraocular pressure (IOP)-lowering effects of NCX 1770, a dual acting new chemical entity with nitric oxide (NO) and phosphodiesterase type-5 (PDE5) inhibitory properties in rabbit and non-human primate models of ocular hypertension and glaucoma
Author Affiliations & Notes
  • Elena Bastia
    Nicox Research Institute, Nicox Research Institute, Bresso, Italy
  • Carol Toris
    University of Nebraska, Omaha, Nebraska, United States
  • Michael V W Bergamini
    North Texas Eye Research Institute, Fort Worth, Texas, United States
    Nicox Ophthalmics, Inc, Durham, North Carolina, United States
  • Stefania Brambilla
    Nicox Research Institute, Nicox Research Institute, Bresso, Italy
  • Corinna Galli
    Nicox Research Institute, Nicox Research Institute, Bresso, Italy
  • Nicoletta Almirante
    Nicox Research Institute, Nicox Research Institute, Bresso, Italy
  • Francesco Impagnatiello
    Nicox Research Institute, Nicox Research Institute, Bresso, Italy
  • Footnotes
    Commercial Relationships   Elena Bastia, Nicox Research Institute (E); Carol Toris, Nicox Research Institute (R); Michael Bergamini, Nicox Research Institute (C); Stefania Brambilla, Nicox Research Institute (E); Corinna Galli, Nicox Research Institute (E); Nicoletta Almirante, Nicox Research Institute (E); Francesco Impagnatiello, Nicox Research Institute (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1232. doi:
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      Elena Bastia, Carol Toris, Michael V W Bergamini, Stefania Brambilla, Corinna Galli, Nicoletta Almirante, Francesco Impagnatiello; Intraocular pressure (IOP)-lowering effects of NCX 1770, a dual acting new chemical entity with nitric oxide (NO) and phosphodiesterase type-5 (PDE5) inhibitory properties in rabbit and non-human primate models of ocular hypertension and glaucoma. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1232.

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Abstract

Purpose : We previously reported on the robust and long-lasting intraocular pressure (IOP)-lowering effects of NCX 1741, a NO-donating avanafil (PDE5 inhibitor) analog in models of ocular hypertension and glaucoma. Here we report on the IOP-lowering effects of NCX 1770, a newly designed single chemical entity optimized to release more NO and a different PDE5 inhibitory scaffold compared to NCX 1741 in naïve rabbits and a non-human primate model of ocular hypertension and glaucoma.

Methods : Laser-induced unilateral ocular hypertensive non-human primates (OHT-monkeys, n=13 eye/group) and ocular normotensive New Zealand White rabbits (ONT-rabbits, n=8-15 eye/group) were used. Vehicle (phosphate buffer pH 6.0, Cremophor EL 5%, DMSO 0.3%, BAC 0.02%) and mirodenafil (PDE5 inhibitor) or NCX 1770 dissolved at equimolar doses in the vehicle were instilled (30μL to OHT-monkeys and 50μL to ONT-rabbits) in a masked, crossover fashion. IOP was determined by pneumatonometry prior to (baseline) and periodically post-dosing.

Results : In ocular OHT-monkeys, mirodenafil (1% or 0.5µmol/eye/30µL) lowered IOP over time reaching a maximum at 3h post-dosing (IOP change vs baseline and vehicle, -5.0±2.1 mmHg). NCX 1770 (1.6% or 0.5µmol/eye/30µL) was more effective than mirodenafil at every time point with the greatest time-matched IOP change at 60min post-dosing (IOP change vs baseline and vs vehicle = -1.9±1.0 and -7.0±0.9 mmHg, for mirodenafil and NCX 1770, respectively). In ONT-rabbits NCX 1770 (1% or 0.5µmol/eye/50µL) effectively decreased the IOP over time (IOP change vs baseline and vs vehicle, -3.4±0.6, -3.8±0.5, -2.2±1.0, -1.9±0.8, -0.6±1.1 and -0.2±0.9 mmHg at 30, 60, 120, 180, 240 and 300min, respectively). These effects were greater than the time-matched IOP changes recorded for equimolar mirodenafil (0.6% or 0.5µmol/eye/50µL) doses (IOP change vs baseline and vs vehicle, -2.6±0.5, -2.5±0.8, -0.7±0.8, 0.3±0.8, -0.2±0.8 and -0.2±0.8 mmHg).

Conclusions : NCX 1770 effectively lowers IOP in ONT-rabbits and OHT-monkeys. In both models the NCX 1770 elicited additional IOP-lowering effects compared to equimolar mirodenafil that is mechanistically attributed to the NO-donating moiety released from NCX 1770.

This is a 2020 ARVO Annual Meeting abstract.

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