Omidenepag isopropyl (OMDI, brand name Eybelis®) is a glaucoma medication classified as a prostanoid EP2 receptor-selective agonist2). It differs from conventional first-line FP receptor agonists (latanoprost, travoprost, tafluprost, bimatoprost) in the receptor it acts on.
OMDI selectively binds to the EP2 receptor and increases intracellular cAMP. This promotes aqueous humor outflow through both the trabecular outflow pathway and the uveoscleral outflow pathway, thereby lowering intraocular pressure1)2).
| Item | Details |
|---|---|
| Generic Name | Omidenepag Isopropyl |
| Receptor | EP2 receptor-selective agonist |
| Concentration and Usage | 0.002%, once daily eye drops |
First approved in the world in Japan in 2018, and also approved by the US FDA in 2024 1). In the Japanese Glaucoma Treatment Guidelines (5th edition), it is positioned as one of the prostanoid receptor-related drugs, and it is stated that “EP2 receptor agonists can also be a first-line choice” 2).
Latanoprost is a prostaglandin-related drug that acts on FP receptors and mainly promotes aqueous humor outflow through the uveoscleral outflow pathway. On the other hand, OMDI acts on EP2 receptors and promotes outflow not only through the uveoscleral outflow pathway but also through the trabecular outflow pathway 2). In addition, a major advantage of OMDI is that it does not cause prostaglandin-associated periorbitopathy (PAP) — iris pigmentation, eyelid pigmentation, eyelash changes, and deepening of the upper eyelid sulcus (DUES) — which are problematic with FP receptor agonists 1)2). The intraocular pressure-lowering effect is equivalent (non-inferior) to latanoprost 1).
The efficacy and safety of OMDI have been evaluated in multiple clinical trials 1).
AYAME Trial (Phase III, Japan)
Design: Randomized, investigator-masked, non-inferiority trial. Japanese patients with primary open-angle glaucoma or ocular hypertension.
Results: The mean diurnal intraocular pressure reduction at 4 weeks with OMDI 0.002% (once daily) was 5.9 mmHg. Non-inferiority to latanoprost 0.005% (6.6 mmHg) was demonstrated 1).
PEONY Trial (Phase III, Asia)
Design: Randomized, investigator-masked, non-inferiority trial. 370 eyes from 4 Asian countries, 3 months 1).
Results: The mean diurnal intraocular pressure reduction in the OMDI group was 7.1 mmHg (28.8%). Non-inferiority to the latanoprost group (7.8 mmHg, 31.3%) was confirmed (between-group difference 0.6 mmHg, 95% CI: 0.0 to 1.2) 1).
RENGE Trial (Phase III, Japan, 12 months) confirmed the long-term efficacy and safety of OMDI 0.002%. Macular edema was observed only in pseudophakic eyes and not in phakic eyes 1).
FUJI Trial examined the efficacy of OMDI in non-responders/low responders to latanoprost. Additional intraocular pressure reduction was obtained by switching to OMDI even in cases with insufficient response to latanoprost 1).
In the PEONY trial, the non-inferiority criterion for OMDI versus latanoprost (upper limit of 95% CI for between-group difference ≤1.5 mmHg) was met at all 9 measurement time points (week 1, week 6, and month 3 at 9:00, 13:00, and 17:00) 1). The intraocular pressure reduction at week 1 was similar in both groups: 6.1 mmHg (24.8%) 1).
In the FUJI study, switching to OMDI 0.002% was evaluated in non-responders or low responders to latanoprost. Since OMDI acts via EP2 receptors, which are different from FP receptors, it may provide additional intraocular pressure reduction even in cases where latanoprost did not achieve sufficient pressure lowering 1). However, although concomitant use of OMDI and FP receptor agonists is not contraindicated, concomitant use with tafluprost is contraindicated 2).
In the PEONY study, the incidence of adverse events was 40.0% in the OMDI group and 29.7% in the latanoprost group 1).
| Adverse Event | OMDI Group | Latanoprost Group |
|---|---|---|
| Conjunctival hyperemia | 11.9% | 5.4% |
| Photophobia | 5.4% | 0.5% |
| Dry eye | 4.9% | 2.2% |
| Corneal thickening | 3.8% | 1.1% |
No serious ocular adverse events were observed in either group1). In the OMDI group, 4 patients discontinued due to adverse events (1 uveitis, 1 iritis, 1 photophobia, 1 foreign body sensation)1).
In the PEONY study, adverse events related to appearance changes (eyelid pigmentation, eyelash thickening, eyelash elongation) were reported only in the latanoprost group1). Since OMDI is an EP2 receptor agonist and does not inhibit adipocyte differentiation, it is thought not to cause deep upper eyelid sulcus (DUES), which is a problem with FP receptor agonists1).
In the adverse event list of the Japanese Glaucoma Practice Guidelines (5th edition), EP2 receptor agonists are described as having no iris/eyelid pigmentation (−) and no eyelash hypertrichosis (−)2).
In the PEONY study, the mean change in central corneal thickness in the OMDI group was +3.4 µm, and no clinically significant corneal edema was observed1). An increase of more than 50 µm was observed in 4 patients (7 eyes), but without corneal edema or visual changes1).
No macular edema was reported in the PEONY study, but the proportion of pseudophakic eyes was low at 10.0% and the observation period was short at 3 months1). Since macular edema was observed only in pseudophakic eyes in a long-term safety study in Japan (RENGE study), intraocular lens-implanted eyes (with posterior capsule rupture) are contraindicated in Japan1)2).
According to the Japanese Glaucoma Practice Guidelines (5th edition), OMDI is contraindicated in (1) aphakic eyes, (2) eyes with intraocular lens implantation and posterior capsule rupture, and (3) concomitant use with tafluprost 2). Because macular edema has been reported in pseudophakic eyes, careful follow-up is required when used in eyes with intraocular lens implantation 1). In addition, since corneal thickening has been reported, caution is needed in patients with reduced corneal endothelial function 1).
OMDI is converted by intraocular esterases to the active metabolite omidenepag. Omidenepag binds with high selectivity to the EP2 receptor (Ki = 3.6 nM, EC50 = 8.3 nM). The EP2 receptor is a G protein-coupled receptor expressed in the ciliary body and trabecular meshwork; its stimulation activates adenylyl cyclase and increases cAMP 1).
The increase in cAMP promotes aqueous humor outflow via the following two pathways:
Uveoscleral outflow pathway: Relaxation of the ciliary muscle and remodeling of the extracellular matrix increase aqueous humor outflow through the uveoscleral outflow pathway 1)2)
Trabecular outflow pathway: Relaxation of trabecular meshwork cells and Schlemm’s canal endothelial cells also increases aqueous humor outflow through the trabecular outflow pathway 1)2)
FP receptor agonists act mainly on the uveoscleral outflow pathway, whereas OMDI acts on both outflow pathways 2). In addition, FP receptor agonists suppress adipogenesis, causing PAP (deepening of the upper eyelid sulcus, periorbital fat atrophy, etc.), whereas EP2 receptor stimulation by OMDI does not suppress adipogenesis, so PAP does not occur 1).
The PEONY study (2024) confirmed the non-inferiority of OMDI to latanoprost in non-Japanese Asian populations (India, Taiwan, Korea, Singapore) 1). In the United States, Phase III SPECTRUM 3/4 trials are comparing OMDI with timolol 1).
OMDI has a clear clinical advantage over FP receptor agonists in avoiding PAP 1). It is expected to be a first-line choice especially for patients concerned about cosmetic side effects or in cases where unilateral treatment causes asymmetry.
Future challenges:
- Wang TH, Aung T, George R, et al. Omidenepag isopropyl versus latanoprost in Asian patients with open-angle glaucoma or ocular hypertension: the phase 3 PEONY study. Clin Ophthalmol. 2024;18:2093-2106.
- 日本緑内障学会. 緑内障診療ガイドライン(第5版). 日眼会誌. 2022;126:85-177.
