NCX 470 Reduces Intraocular Pressure More Effectively Than Lumigan in Dogs and Enhances Conventional and Uveoscleral Outflow in Non-Human Primates and Human Trabecular Meshwork/Schlemm’s Canal Constructs

Abstract

Purpose: To determine NCX 470 (0.1%) and Lumigan® (bimatoprost ophthalmic solution, 0.01%—LUM) intraocular pressure (IOP)-lowering activity after single or repeated (5 days) dosing along with changes in aqueous humor (AH) dynamics. Methods: Ocular hypotensive activity of NCX 470 and LUM was compared with vehicle (VEH) in Beagle dogs using TonoVet®. Non-human primates (NHP) and bioengineered three-dimensional (3D) human Trabecular Meshwork/Schlemm’s Canal (HTM/HSC™) constructs exposed to transforming growth factor-b2 (TGFb2) were used to monitor NCX 470 and LUM-induced changes in AH dynamics. Results: NCX 470 (30 mL/eye) showed greater IOP reduction compared with LUM (30 mL/eye) following single AM dosing [maximum change from baseline (CFBmax) = -1.39 – 0.52, -6.33 – 0.73, and -3.89 – 0.66 mmHg (mean – standard error of the mean) for VEH, NCX 470, and LUM, respectively]. Likewise, repeated 5 days daily dosing of NCX 470 resulted in lower IOP than LUM across the duration of the study (average IOP decrease across tests was -0.45 – 0.22, -6.06 – 0.15, and -3.60 – 0.22 mmHg for VEH, NCX 470, and LUM, respectively). NCX 470 increased outflow facility (Cfl) in vivo in NHP (CflVEH = 0.37 – 0.09 mL/min/mmHg and CflNCX470 = 0.64 – 0.17 mL/min/mmHg) as well as in vitro (CHTM/HSC) in HTM/HSC constructs (CHTM/HSC_VEH = 0.47 – 0.02 mL/min/mm2/mmHg and CHTM/HSC_NCX470 = 0.76 – 0.03 mL/min/mm2/mmHg). In addition, NCX 470 increased uveoscleral outflow (FuVEH = 0.62 – 0.26 mL/min and FuNCX470 = 1.53 – 0.39 mL/min with episcleral venous pressure of 15 mmHg) leaving unaltered aqueous flow (AHFVEH = 2.03 – 0.22 mL/min and AHFNCX470 = 1.93 – 0.31 mL/min) in NHP. Conclusions: NCX 470 elicits greater IOP reduction than LUM following single or repeated dosing. Data in NHP and 3D-HTM/HSC constructs suggest that changes in Cfl and Fu account for the robust IOP-lowering effect of NCX 470.