Topical Omidenepag Isopropyl in Glaucoma Management

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Article initiated by:

Abdelrahman M. Elhusseiny, MD, MSc, Kaersti L. Rickels

All contributors:

Ahmad A. Aref, MD, MBA, Ahmad A. Aref, MD, MBA, Abdelrahman M. Elhusseiny, MD, MSc, Mari Ogino, MD

Assigned editor:

Review:

Assigned status Update Pending

 by Ahmad A. Aref, MD, MBA on December 23, 2023.

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Contributing Editors:	add

Introduction:

Various selective E-prostanoid subtype 2 (EP2) agonists such as taprenepag isopropyl, aganepag isopropyl, and omidenepag isopropyl (OMDI) are currently under investigation as topical intraocular pressure (IOP) lowering medications in the management of glaucoma and ocular hypertension.

The OMDI ophthalmic solution 0.002% (Eybelis, Santen Pharmaceutical Co., Ltd., Osaka, Japan) works by increasing aqueous humor drainage through the trabecular and uveoscleral outflow pathways. OMDI was first introduced in Japan in November 2018, with approval and release following in five countries and regions by February 2021.

Unlike prostaglandin analogs working on F-prostanoid (FP) receptor, OMDI has not been associated with periorbitopathy with comparable IOP-lowering effects to prostaglandin analogs.

Mechanism of action:

Upon corneal penetration, OMDI is hydrolyzed to its active metabolite (omidenepag, OMD), which behaves as a non-prostaglandin selective EP2 receptor agonist. This EP2 receptor has Gs-coupled transmembrane properties within the ciliary body and trabecular meshwork (TM). When OMD is bound, this stimulates an increase in intracellular adenosine 3’,5-cyclic monophosphate (cAMP) levels through Gs-protein-mediation and other signaling cascades in the ciliary body and TM. This increased cAMP level promotes aqueous humor outflow by increasing trabecular and uveoscleral outflow.

Pharmacokinetics:

OMDl undergoes rapid hydrolysis to the metabolically active OMD. OMI binds to the EP2 receptor with a strong affinity of K_i = 3.6nM and high agonistic activity with E_c = 8.3nM. It has no activity towards the prostaglandin E1 receptor (EP1) nor the prostaglandin F receptor (FP). Although the mean terminal half-life of OMDI is unknown at this time, the half-life of OMD is approximately 30 minutes.

Dosage and Administration:

OMDI recommended dosage is one drop in the affected eye(s) nightly. The bottle should be shaken prior to instillation and if other drops are used in conjunction with OMDI, these should be administered at least 5 minutes apart.

Adverse Reactions:

According to multiple clinical trials, some of which are discussed in the following section, the most common adverse reactions include conjunctival hyperemia, photophobia, blurry vision, dry eyes, instillation site pain, eye pain, ocular hyperemia, punctate keratitis, headache, eye irritation, and vision loss.

Other clinically significant side effects that should be reviewed with patients prior to prescribing OMDI include iris pigmentary changes, increased eyelash growth, ocular inflammation, and macular edema.

The iris pigmentation is likely to be permanent following discontinuation of OMDI. The eyelash changes and periorbital tissue pigmentary changes are likely reversible following discontinuation of OMDI. Cases of ocular inflammation have been reported in patients using OMDI. It may be prudent to take this into account if patients have risk factors for or already have ocular inflammatory disease like iritis or uveitis. Macular edema (CME) has been reported in clinical trials in patients who were aphakic or pseudophakic. OMDI should be used with caution in aphakic or pseudophakic patients or in those with increased risk of CME development.

Efficacy and Safety:

Table 1 summarizes the studies evaluating the efficacy of OMDI in glaucoma management. Phase II of clinical trials performed by Aihara et al. revealed that the most effective concentration of OMDI was 0.002% once daily when comparing OMDI to latanoprost 0.0005% and placebo. Olander et al. determined that a once-daily dose, when compared to twice-daily dosing, had no significant difference in IOP reduction (−0.60 ± 0.60 mmHg; 95% CI, −1.80 to 0.59; P = 0.3199), but adverse events (AEs) were much more common in the twice-daily arm of the study affecting 41.7% of patients while only 14.0% of patients in the once-daily arm experienced AEs, therefore making a once daily the preferred dose.

The AYAME study compared OMDI at 0.002% to latanoprost 0.005% once-daily and found that the OMDI was just as well tolerated and not inferior at reducing IOP in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). In the OMDI group, they reported a significant IOP reduction from a mean of 23.78 ± 1.73 mmHg at baseline to 17.81 ± 2.41 mmHg at week 4. On the other hand, in the latanoprost group, the IOP was significantly reduced from a mean of 23.40 ± 1.51 mmHg at baseline to 16.96 ± 2.24 mmHg at week 4. The difference in the mean IOP reduction between both groups was statistically significant (P=0.048); however, it was a very small difference (0.63 ± 0.32 mmHg). The AEs from OMDI reported included conjunctival Hyperemia as the most common treatment-related ocular AE affecting 23 patients (24.5%) in the OMDI group and 10 patients (10.4%) in the latanoprost group. This was followed by corneal thickening, affecting 11 patients (11.7%) in the OMDI group and 1 patient (1.0%) in the latanoprost group, and then photophobia, affecting 4 patients (4.3%) in the OMDI group. There were 5 (5.2%) cases of punctate keratitis related to treatment reported in the latanoprost group, which was not observed in the OMDI group.

A retrospective study by Inoue et al. evaluated the efficacy of OMDI in 54 eyes with normal-tension glaucoma (NTG). They reported a significant IOP reduction from a mean of 15.7 mmHg at baseline to 12.0 mmHg after 4 months of OMDI use (P<0.0001). The most reported AEs were conjunctival hyperemia (5.6%) and eye pain (1.9%). Miki et al., in a multicenter retrospective study, also showed the potential for OMDI to decrease IOP in both POAG and secondary glaucoma patients. By evaluating 827 patients, they found a mean reduction in IOP of –2.5 ± 2.9 mmHg after 12 weeks of treatment. The most common AE was conjunctival hyperemia in 7.6% of patients, followed by eye itching in 1.9% and vision blurriness in 1.1%.

One prospective study by Shiratori et al. evaluated 25 patients with untreated POAG or OHT and found that using OMDI had an average IOP reduction of -3.4 ± 3.9 mmHg over 4 weeks. Similar AEs were reported as previous studies, including mild conjunctival hyperemia (32%), and mild iritis (4%). Another prospective study found that this agent may. be effective in latanoprost low/non-responders.

A systemic review by Matuso et al. demonstrated that OMDI, compared to FP receptor agonists, such as latanoprost, had little to no prostaglandin-associated periorbitopathy (PAP) side effects, including eyelid pigmentation, eyelash growth, or deepening of the upper eyelid sulcus. In latanoprost-poor responders, OMDI still had a stable IOP-lowering effect.

Table 1. Summary of the major studies evaluating the efficacy of omidenepag isopropyl (OMDI) in glaucoma management

POAG: primary open-angle glaucoma, OHT: ocular hypertension, NTG: normal tension glaucoma, PACG: primary angle-closure glaucoma, AC: anterior chamber

Study	Study Design	Number of Study Eyes (or Patients)	Type of Glaucoma	Mean Age of Study Population	Follow-up Period	Baseline IOP (mmHg)	IOP at last follow-up (mmHg)	Most Common Adverse Effects
Aihara et al. NCT01868126 & NCT02179008 (SEE-1)	Phase II study comparing different concentrations of OMDI	91 patients	POAG or OHT	65.27 +/- 11.2 years	12 weeks	OMDI 0.0003%: 24.6 OMDI 0.0001%: 24.8 OMDI 0.0012%: 25.1 OMDI 0.0016%: 25.5 OMDI 0.002%: 24.8 OMDI 0.0025%: 25.6 OMDI 0.003%: 25.8 Latanoprost: 25.5 Placebo: 25.5	OMDI 0.0003%: 21.48 OMDI 0.0001%: 20.21 OMDI 0.0012%: 20.93 OMDI 0.0016%: 20.81 OMDI 0.002%: 17.41 OMDI 0.0025%: 19.62 OMDI 0.003%: 19.81 Latanoprost: 17.73 Placebo: 23.56	Conjunctival hyperemia
SPECTRUM 6 Olander et al.	Phase II study	98 patients	POAG or OHT	66.79 +/- 9.0 years	6 weeks	OMDI QD: 24.55 OMDI BID: 25.39	OMDI QD: 18.37 OMDI BID: 17.77	Ocular hyperemia, iritis, nausea, conjunctival hyperemia, ocular discomfort
Ayame Study- Aihara et al.	Phase III, randomized noninferiority study comparing OMDI 0.002% vs. Latanoprost 0.005%	190 patients	POAG or OHT	63.6 +/-11.9 years	Days 29 +/- 3	OMDI 0.002%: 23.78 ± 1.73 Latanoprost: 23.40 ± 1.51 Placebo: 23.4	OMDI: 17.81 ± 2.41 Latanoprost: 16.96 ± 2.24 Placebo: 21.22	In the OMDI group: Conjunctival hyperemia (24.5%), corneal thickening (11.7%)
FUJI study- Aihara et al.	Phase III study	26 patients	POAG or OHT who were non-/poor responders to Latanoprost	64.4 +/- 11.0 years	16 weeks	23.1	20.13 end of washout; 20.11 from end of latanoprost run in	AC cell, conjunctival hyperemia, and erythema of eyelid
RENGE study- Aihara et al.	Phase III study	125 patients	POAG or OHT Cohort 1: IOP ≥16 - <22 mmHg Cohort 2 and 3: ≥22 mmHg - ≤34 mmHg	65.2 +/- 10.0 years	52 weeks	Cohort 1: 18.71 Cohort 2: 24.06 Cohort 3: 23.14	Cohort 1: 15.01 Cohort 2: 18.46 Cohort 3: 14.74	Conjunctival hyperemia, macular edema
Shiratori et al.	Prospective	25 patients	POAG or OHT	52.2 +/- 8.5 years	4 weeks	18.7 ± 2.2	15.6 ± 2.4	Mild conjunctival hyperemia (32%), mild iritis (4%)
Inoue et al.	Retrospective	54 eyes	NTG	55 +/- 14.1 years	16 weeks	15.7 ± 2.6	After 1-2 months: 13.5 +/- 2.3 After 3-4 months: 13.6 +/- 2.4	Conjunctival hyperemia (5.6%), eye pain (1.9%)
Miki et al.	Retrospective	827 patients	POAG, NTG, PACG, secondary glaucoma, or OHT	61.7 +/- 13.2 years	12 weeks	15.8 ± 4.4	14.0 ± 3.3 in the naïve monotherapy group	Ocular hyperemia (7.6%), ocular itching (1.9%), and Blurry vision (1.1%)

Conclusion:

The OMDI is a novel IOP-lowering medication with efficacy comparable to prostaglandin analogs. It was effective even in latanoprost poor responders with minimal or no PAP.