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Editors Selection IGR 17-4

Medical Treatment: Can a selective EP2-antagonist avoid PAPS?

Comment by Niklas Telinius & Miriam Kolko on:

96033 Prostaglandin-associated periorbitopathy syndrome (PAPS): Addressing an unmet clinical need, Sakata R; Chang PY; Sung KR et al., Seminars in Ophthalmology, 2021; 0: 1-8

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Topical prostaglandin-analogues (PGA) are the preferred first-line treatment for glaucoma. Although these drugs are well tolerated in general, some patients develop PGA specific side-effects. Prostaglandin-associated periorbitopathy syndrome (PAPS) comprise 10 different clinical and cosmetic signs that PGA treatment can result in. Some of the most prominent findings is deepening of the upper eyelid sulcus, orbital fat atrophy, ciliary hypertrichosis and hyperpigmentation of the periorbital skin. In the article by Sakata et al the authors provide a detailed review of the clinical findings and the underlying mechanisms. PAPS may be reversed by discontinuation of the PGA but this is not always an option as IOP may rise. A solution to this clinical dilemma is the focus of the second part of the review. In the second part the authors present a new non-prostaglandin selective EP2 agonist, omidenepag isopropyl (OMDI). The drug hydrolyses during corneal penetration to an active EP2 agonist metabolite. The binding to the EP2 receptor results in a different mechanism of action compared to conventional PGA, which bind to the FP_2α receptor. The difference in receptor selectivity results in no stimulation of eyelash growth and no inhibition adipogenesis. Small case series have shown that switching patients with PAPS from PGA treatment to OMDI result in improvement in PAPS symptoms. The IOP-lowering effect of OMDI is achieved through increased outflow via the conventional outflow pathway and the uveo-scleral outflow pathway, just as with PGA. In clinical studies patients treated with OMDI achieved clinically relevant IOP reductions. The efficacy of OMDI compared to conventional PGA is not completely clear at the moment but is addressed in an ongoing Phase III study (PEONY study). The PEONY study is designed as a non-inferiority study, where 370 patients are randomized to latanoprost or OMDI and followed for three months.

Switching patients with PAPS from PGA treatment to OMDI result in improvement in PAPS symptom

Currently, OMDI is only available in Japan, where it was approved by the authorities in 2018. It is expected that it will be available in more countries in the near future. There is always room for another clinical effective IOP-lowering drug with a favorable side effect profile. PGA have been on the market for over two decades, but the consequences of longterm exposure take many years to discover (PAPS was defined in 2012). Future studies will therefore be important to determining the clinical efficacy and side effects of OMDI.

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