A novel selective soluble guanylate cyclase activator MGV354, lowers intraocular pressure in preclinical models following topical ocular dosing

Abstract

Purpose : The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) has been known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. Oxidative stress confers greater susceptibility of anterior chamber tissues particularly in the trabecular meshwork (TM) and Schlemm’s canal (SC) that can result in dysfunction of the outflow pathway. Oxidation of the prosthetic heme on the β subunit of sGC can render the enzyme unresponsive to NO and in the TM/SC can lead to increased resistance to aqueous humor outflow. We have identified a specific molecule, MGV354 that can generate cGMP from heme-free, NO-independent oxidized sGC in human TM cells and have evaluated its in-vivo efficacy.

Methods : Immunohistochemistry of ocular tissues (human/cynomolgus monkey) was used to detect sGC expression. Cyclic GMP levels were evaluated in human TM cells with MGV354 treatment in the presence of an oxidizing agent, ODQ. IOP changes and exposure studies were performed in rabbits and laser trabeculoplasty-induced ocular hypertensive cynomolgus monkeys following top-oc dosing.

Results : sGC was highly expressed in the human and cynomolgus monkey outflow pathway. A single topical ocular dose with MGV354 in Dutch-belted rabbits caused a significant reduction in IOP by ~20% (vs. vehicle) lasting up to 6h whereas a dose-dependent IOP reduction 25-40% (vs. vehicle) lasting up to 24h post-dose was observed in a cynomolgus monkey model of glaucoma. MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in the cynomolgus monkey model of glaucoma, which appeared to be better than that observed with travoprost, a prostaglandin FP agonist (standard of care). Mild to moderate ocular hyperemia was the main adverse effect noted post-dose in rabbits and monkeys.

Conclusions : With high ocular exposure and low systemic exposure following topical dosing, MGV354 represents a novel class of sGC activators which can lower IOP in preclinical models of glaucoma. The potential for sGC activators as effective IOP lowering drugs in ocular hypertensive and/or glaucoma patients could be further determined in clinical studies and may represent a new class of compounds in the armamentarium of IOP lowering medications.

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