Topical Omidenepag Isopropyl in Glaucoma Management

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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. [1] 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. [2]

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. [2] 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.

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.[3] 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. [4]

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). [5] 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). [6] 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.[7] 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. [8] Similar AEs were reported as previous studies, including mild conjunctival hyperemia (32%), and mild iritis (4%).

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. [2] 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.[3]

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%:


OMDI 0.0016%:


OMDI 0.002%: 24.8

OMDI 0.0025%:


OMDI 0.003%: 25.8

Latanoprost: 25.5

Placebo: 25.5

OMDI 0.0003%:


OMDI 0.0001%: 20.21

OMDI 0.0012%:


OMDI 0.0016%:


OMDI 0.002%: 17.41

OMDI 0.0025%:


OMDI 0.003%: 19.81

Latanoprost: 17.73

Placebo: 23.56

Conjunctival hyperemia
SPECTRUM 6 Olander et al.[4] 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. [5] 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


23.40 ± 1.51

Placebo: 23.4

OMDI: 17.81 ± 2.41


16.96 ± 2.24

Placebo: 21.22

In the OMDI group: Conjunctival hyperemia (24.5%), corneal thickening (11.7%)
FUJI study- Aihara et al. [9] 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. [10] 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. [8] 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. [6] 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. [7] 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%)


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.


  1. Santen Pharmaceutical Co., Ltd. and UBE Corporation. (September 2022). Santen and UBE Received FDA Approval for OMLONTI® (Omidenepag Isopropyl Ophthalmic Solution) 0.002% for the Reduction of Elevated Intraocular Pressure in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension [Press release].  
  2. 2.0 2.1 2.2 Matsuo M, Matsuoka Y, Tanito M. Efficacy and Patient Tolerability of Omidenepag Isopropyl in the Treatment of Glaucoma and Ocular Hypertension. Clin Ophthalmol. 2022 Apr 26;16:1261-1279. doi: 10.2147/OPTH.S340386. PMID: 35510270; PMCID: PMC9058248.
  3. 3.0 3.1 Aihara M, Lu F, Kawata H, Iwata A, Liu K, Odani-Kawabata N, Shams NK. Phase 2, Randomized, Dose-finding Studies of Omidenepag Isopropyl, a Selective EP2 Agonist, in Patients With Primary Open-angle Glaucoma or Ocular Hypertension. J Glaucoma. 2019 May;28(5):375-385. doi: 10.1097/IJG.0000000000001221. PMID: 30839416.
  4. 4.0 4.1 Olander K, Sato MA, Abrams MA, Jerkins GW, Lu F, Dinh P, Odani N, Chabi A, Shams NK; A randomized Phase 2 trial assessing the safety and efficacy of omidenepag isopropyl 0.002% once and twice daily in subjects with primary open-angle glaucoma or ocular hypertension (Spectrum 6). Invest. Ophthalmol. Vis. Sci. 2020;61(7):4258.
  5. 5.0 5.1 Aihara M, Lu F, Kawata H, Iwata A, Odani-Kawabata N, Shams NK; Omidenepag Isopropyl Versus Latanoprost in Primary Open-Angle Glaucoma and Ocular Hypertension. Am. J. Ophthalmol. 2020;220:53-63
  6. 6.0 6.1 Inoue K, Inoue J, Kunimatsu-Sanuki S, Nozaki N, Shimizu K, Ishida K, Tomita G. Short-Term Efficacy and Safety of Omidenepag Isopropyl in Patients with Normal-Tension Glaucoma. Clin Ophthalmol. 2020 Sep 30;14:2943-2949. doi: 10.2147/OPTH.S271789. PMID: 33061280; PMCID: PMC7533234.
  7. 7.0 7.1 Miki A, Miyamoto E, Ishida N, Shii D, Hori K; LESPOIR Research Group. Efficacy and Safety of Omidenepag Isopropyl 0.002% Ophthalmic Solution: A Retrospective Analysis of Real-World Data in Japan. Adv Ther. 2022 May;39(5):2085-2095. doi: 10.1007/s12325-022-02069-6. Epub 2022 Mar 14. PMID: 35287233; PMCID: PMC9056475.
  8. 8.0 8.1 Shiratori N, Nishio Y, Takeda A, Sugimoto S, Takazawa K, Otsuka N, Ishida N, Shii D, Hori K, Nakamoto K. Twenty-Four-Hour Intraocular Pressure Control with Omidenepag Isopropyl 0.002% in Patients with Glaucoma and Ocular Hypertension. Clin Ophthalmol. 2021 Oct 4;15:3997-4003. doi: 10.2147/OPTH.S333042. PMID: 34675468; PMCID: PMC8500489.
  9. Aihara M, Ropo A, Lu F, Kawata H, Iwata A, Odani-Kawabata N, Shams N. Intraocular pressure-lowering effect of omidenepag isopropyl in latanoprost non-/low-responder patients with primary open-angle glaucoma or ocular hypertension: the FUJI study. Jpn J Ophthalmol. 2020 Jul;64(4):398-406. doi: 10.1007/s10384-020-00748-x. Epub 2020 Jun 22. PMID: 32572719.
  10. Aihara M, Lu F, Kawata H, Iwata A, Odani-Kawabata N. Twelve-month efficacy and safety of omidenepag isopropyl, a selective EP2 agonist, in open-angle glaucoma and ocular hypertension: the RENGE study. Jpn J Ophthalmol. 2021 Nov;65(6):810-819. doi: 10.1007/s10384-021-00868-y. Epub 2021 Sep 8. PMID: 34495425.
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