Characterization of SHP639, a novel topical C-type natriuretic peptide analog, on intraocular pressure and aqueous humor dynamics in mice

Abstract

Purpose : Natriuretic peptide receptor type B (NPR-B) agonists, such as C-type natriuretic peptide (CNP), lower intraocular pressure (IOP) in animal models when injected intraocularly. SHP639 is a topical 9-amino acid, synthetic, CNP analog in Phase 1 development for the treatment of glaucoma and ocular hypertension. We assessed the effects of SHP639 on mouse IOP and aqueous humor (AH) dynamics (AH outflow, AH formation and episcleral venous pressure) after topical ocular administration.

Methods : Ligand binding assays of SHP639 to 89 receptors and transporters were conducted by NovaScreen. NPR-B activation was evaluated by cyclic GMP production in cultured transformed human trabecular meshwork cells (GTM-3 cells). Conscious mouse IOP measurements were performed with a TonoLab^® rebound tonometer. Mouse AH dynamics were evaluated by an in vivo constant-flow infusion method.

Results : At 10 µM, SHP639 inhibited ligand binding by >50% in 2 of the 89 receptors and transporters tested. SHP639 interacted with the type 2 angiotensin (AT2) receptor (IC₅₀ = 8 µM) and the cholecystokinin A (CCK-A or CCK1) receptor (IC₅₀ = 26 µM). In GTM-3 cells, SHP639 potently and efficaciously activated NPR-B with an EC₅₀ of 61 ± 11 nM (mean ± SD, n = 17) and an E_max of 106 ± 11% (similar to the E_max of CNP, which defined 100%). SHP639 activated NPR-A with an EC₅₀ of 2179 ± 670 nM (36 times more potent for NPR-B than for NPR-A). Topical ocular administration (5 μl) of SHP639 significantly lowered IOP in a dose-dependent manner: –12.1%, –21.1% and –36.1% for the 0.1%, 0.3% and 0.6% doses respectively (p<0.05 for all SHP639 doses vs. vehicle at each time point). Duration of action was >6 h and the maximum effects were observed at 2 h after topical ocular administration for all doses. At 2 h, 0.6% SHP639 significantly increased outflow facility (+155.8%, Figure), and decreased AH flow rate (–41.0%), uveoscleral outflow rate (–52.6%) and episcleral venous pressure (–31.5%; p<0.05 for all parameters SHP639 vs. vehicle). No adverse effects were observed in the SHP639-treated mice.

Conclusions : SHP639 is a selective NPR-B agonist and an efficacious topical IOP-lowering agent. Its mechanism of action has a unique combination of reducing aqueous production and increasing outflow, both of which contribute to the IOP-lowering effect.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

Figure. 0.6% SHP639 increased outflow facility in mice