A Novel Selective Soluble Guanylate Cyclase Activator, MGV354, Lowers Intraocular Pressure in Preclinical Models, Following Topical Ocular Dosing

  • Invest Ophthalmol Vis Sci. 2018 Apr 1;59(5):1704-1716. doi: 10.1167/iovs.18-23772.
Ganesh Prasanna  1 ,  Luciana Ferrara  1 ,  Christopher Adams  2 ,  Takeru Ehara  2 ,  Byron Li  1 ,  Louis Yang  1 ,  Chuanxi Xiang  1 ,  Christopher Thow Hing Ng  3 ,  Sean Kim  4 ,  Christopher Towler  5 ,  Todd Topley  5 ,  Cale McAllister  5 ,  Malay Ghosh  5 ,  Ronald Newton  6 ,  Rebecca Stacy  7 ,  Dennis S Rice  1 ,  Muneto Mogi  2
Affiliations
  • 1. Ophthalmology Research, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.
  • 2. Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.
  • 3. Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.
  • 4. Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.
  • 5. Technical Research & Development, Global Drug Development, Fort Worth, Texas, United States.
  • 6. Preclinical Safety, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.
  • 7. Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.
PMID: 29610853 DOI: 10.1167/iovs.18-23772
Abstract

Purpose: The nitric oxide/soluble Guanylate Cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate.

Methods: Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354.

Results: sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted.

Conclusions: MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies.

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