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Editors Selection IGR 10-3

Basic science: Insights into the pharmacology of a selective EP2-R agonist

Comment by Makoto Aihara on:

106832 Downregulation of COL12A1 and COL13A1 by a selective EP2 receptor agonist, omidenepag, in human trabecular meshwork cells, Kumon M; Fuwa M; Shimazaki A et al., PLoS ONE, 2023; 18: e0280331

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Omidenapag (OMD) isopropyl (OMDI), a novel IOP-lowering drug, was developed and launched first in Japan and has since been approved in Asian countries and US. Its IOP-lowering effect is through the prostanoid EP2 receptor and has been shown to be non-inferior to latanoprost, an FP agonist. OMD is the first drug in the last two decades with a completely new mechanism of action (MOA) that has comparable efficacy to latanoprost. OMD is a selective prostanoid EP2 receptor agonist and has no prostaglandin structure. Thus, OMD has no binding to the FP receptor or the other prostanoid receptors. EP2 and FP receptors are G-protein coupled-receptors, but their intracellular signals are completely different. FP receptor coupled Gq, whereas EP2 receptor coupled Gs. Therefore, OMD, a selective EP2 receptor agonist, has a different MOA and adverse reactions from FP agonists. In terms of aqueous humor dynamics, OMD enhances both conventional and uveoscleral outflow. But its molecular mechanism has not been fully clarified.

OMD is the first drug in the last two decades with a completely new mechanism of action (MOA) that has comparable efficacy to latanoprost

Kumon et al. examined the effect of OMD on seven kinds of extracellular matrix and 15 kinds of MMP and TIMPs, using 2D and 3D cultures of human trabecular meshwork cells. This study was well organized in the cell identification, the dose-dependency of the drug, the number of targeted molecules regarding ECM and related enzymes, and the repeatability. At first, its effect was investigated in 2D culture, and as a next step, the target molecules were certified using 3D cell culture mimicking the in vivo histological condition. They found that COL12A1 and COL13A1 was decreased by the stimulation of OMD in a dose-dependent manner in both 2D and 3D culture conditions. In conclusion, a new drug, OMD may enhance aqueous humor outflow through the reduction of trabecular tissue resistance. Of course, since this has not been clarified in vivo, the MOA of IOP reduction may be more complicated. Also, the MOA in the uveoscleral outflow pathway should be investigated in future.

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