One-Year Efficacy and Safety of Omidenepag Isopropyl in Patients with Normal-Tension Glaucoma

Abstract

Purpose:

To retrospectively evaluate the 1-year efficacy and safety of single-agent of omidenepag isopropyl in patients with normal-tension glaucoma (NTG).

Methods:

One hundred patients (100 eyes) newly administered omidenepag isopropyl were enrolled. Intraocular pressure (IOP) was compared at baseline and 3, 6, 9, and 12 months after administration. The mean deviation values at baseline and 12 months measured using the Humphrey visual field test (30-2 Swedish Interactive Threshold Algorithm standard) were compared. Adverse reactions and dropouts were observed.

Results:

IOP significantly decreased from 15.5 ± 2.7 mmHg at baseline to 13.3 ± 2.5 mmHg after 3 months, 13.7 ± 2.3 mmHg after 6 months, 13.9 ± 2.4 mmHg after 9 months, and 13.7 ± 2.3 mmHg after 12 months (P < 0.0001). There was no significant difference in the mean deviation values at baseline (−3.66 ± 3.49 dB) and after 12 months (−3.41 ± 3.80 dB). Adverse reactions occurred in 9 patients (9.0%): conjunctival hyperemia (n = 6), eye pain (n = 1), iritis (n = 1), and blepharitis (n = 1). Twenty-one patients (21.0%) discontinued administration because of changes in medication (n = 7), interruption of visits (n = 5), adverse reactions (n = 4), and others.

Conclusions:

After administering omidenepag isopropyl, the IOP in patients with NTG decreased within 1 year, visual fields were maintained, and safety was satisfactory. Omidenepag isopropyl can be used as the first-line medication for patients with NTG.

Introduction

The purpose of treating glaucoma is to stop or slow down the progression of visual field defects, and lowering of the intraocular pressure (IOP) is the only treatment with evidence.^1,2 The treatments for lowering IOP include eye drops, oral medicines, laser treatments, and surgery. Initially, a single-agent eye drop is administered.³ Prostaglandin analog eye drops are the first-line medication because they have a strong efficacy in lowering IOP. However, they can cause topical periocular adverse reactions, including eyelid pigmentation, iris pigmentation, eyelash growth, and deepening of the upper eyelid sulcus.^4,5

The ideal eye drop should have the same IOP-lowering effect and fewer ocular adverse reactions as prostaglandin analogs. Based on this, omidenepag isopropyl, which has the above characteristics, has been approved for the treatment of glaucoma in Japan since November 2018.^6–10 It is necessary to investigate the applicability of omidenepag isopropyl as the first-choice medication for glaucoma treatment.

We previously reported the IOP-lowering effects and safety of omidenepag isopropyl over 3 months for patients with normal-tension glaucoma (NTG)¹¹ as a common type of glaucoma in Japan.¹² That study indicated that omidenepag isopropyl has strong efficacy in lowering IOP and high safety in the short term. It is important to evaluate the efficacy and safety of the long-term administration of omidenepag isopropyl because glaucoma treatment is a long-term process. However, reports are lacking on this.

In this study, the long-term efficacy and safety of single-agent of omidenepag isopropyl in patients with NTG were retrospectively investigated.

Methods

One hundred patients (100 eyes) with NTG treated at the Inouye Eye Hospital Group (Inouye Eye Hospital, Nishikasai Inouye Eye Hospital, Omiya Inouye Eye Clinic, and Sapporo Inouye Eye Clinic) were administered omidenepag isopropyl (EYBELIS ophthalmic solution 0.002%, Santen Pharmaceutical Co., Ltd., Japan) between December 2018 and September 2020. All patients were previously untreated with any IOP-lowering drug before commencing treatment with omidenepag.

The diagnostic criteria used for NTG were as follows: (1) typical morphological characteristics, such as thinning of the optic disc rim and defects in the retinal nerve fiber layer; (2) an abnormal visual field with high reliability and reproducibility, which corresponds to the criteria outlined (1); (3) exclusion of other eye diseases or congenital abnormalities that could cause an abnormal visual field; (4) a primary open-angle on gonioscopy; and (5) an IOP of ≤21 mmHg on serial measurements allowing for diurnal variation.

The patients were administered omidenepag isopropyl once daily in the eye every morning. According to our institution's normal practice, we advised patients to administer the eye drop in the morning, as it is easier at this time to confirm the awareness of symptoms because it is considered that patients are relatively less aware of adverse reaction symptoms when they use the eye drop in the night.

All adverse reactions were to be reported if they were recorded during the observation period of the current study since adverse reactions were either declared by the patient or determined by the physician on the date of each visit or were recorded in the medical record if the patient contacted the hospital to report an adverse reaction.

Information regarding the IOP values was measured using the Goldmann tonometer, mean deviation values were measured using the Humphrey visual field test program (30-2 Swedish Interactive Threshold Algorithm standard), and adverse reactions and dropouts after admission were retrospectively retrieved from the patients' medical records.

The IOPs were compared at baseline and 3, 6, 9, and 12 months after initial administration. The IOP reductions and reduction rates from baseline to 3, 6, 9, and 12 months were calculated. The mean deviation values at baseline and 12 months after administration were compared. For patients with both eyes satisfying the inclusion criteria, the eye with the higher IOP at baseline was enrolled; if the IOP was the same in both eyes, the right eye was enrolled.

The sample size was calculated using the R statistical software, version 4.1.0. (R Development Core Team, Vienna, Austria). As a result, 64 patients were required to achieve a significance level (alpha) of 0.05 and a power (1–β) of 0.9.¹³ The number of patients in this study was collected on this basis, resulting in 100 patients.

Changes in IOP were analyzed using analysis of variance and Bonferroni correction. Comparisons of IOP reduction and the IOP reduction rate were analyzed using Friedman's test and the Wilcoxon signed-rank test. The mean deviation values were compared and analyzed using the Wilcoxon signed-rank test. Statistical analyses for IOP and mean deviation values were conducted using IBM SPSS-Statistics 22 (IBM Corp., Armonk, NY). The listwise deletion offered by such statistical software was used for all variables with missing values. Statistical significance was set at P < 0.05.

The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Inouye Eye Hospital Ethics Committee.

The study information was provided at the hospital, and participants had the opportunity to refuse inclusion in the study.

Results

The participants included 36 men and 64 women. The mean age was 55.3 ± 12.8 years (mean ± standard deviation; range, 22 − 83 years). The mean IOP at baseline was 15.5 ± 2.7 mmHg (range, 10−21 mmHg). The mean deviation value for the 100 patients measured using the Humphrey visual field test program (30-2 Swedish Interactive Threshold Algorithm standard) was −3.66 ± 3.49 dB (range, −16.10 to 2.28 dB).

The result of IOP measurements is shown in Table 1. The IOPs significantly decreased after 3 and 6 months compared to baseline (P < 0.0001). The mean deviation value assessed using the Humphrey visual field test was −3.66 ± 3.49 dB at baseline and −3.41 ± 3.80 dB after 12 months; there was no significant difference (P = 0.1226).

Table 1.

Intraocular Pressure Measurements

	IOP (mmHg)	IOP reduction (mmHg)	IOP reduction rate (%)
Baseline	15.5 ± 2.7	—	—
After 3 months	13.3 ± 2.5^**	2.1 ± 1.9	13.2 ± 11.9
After 6 months	13.7 ± 2.3^**	1.5 ± 2.0	8.8 ± 13.2
After 9 months	13.9 ± 2.4^**	1.5 ± 2.0	8.6 ± 12.1
After 12 months	13.7 ± 2.3^**	1.6 ± 2.3	9.3 ± 13.8

P < 0.0001.

IOP, intraocular pressure.

Adverse reactions occurred in 9 patients (9.0%) (Table 2). Loss of visual acuity by 2 or more lines was observed in 1 patient (1.0%); progression of cataract was the underlying cause of loss of visual acuity in this patient. There was no cystoid macular edema, as evident on optical coherence tomography. Eyelid pigmentation, eyelash growth, and deepening of the upper eyelid sulcus—all particular to treatment with prostaglandin analog eye drops—were not observed.

Table 2.

Adverse Reactions After Administration of Omidenepag Isopropyl

Adverse reaction	No. of patients	Progress: number
Conjunctival hyperemia	6 (6.0%)	Discontinuation of administration: 2 (after 1 and 2 weeks, respectively)
Conjunctival hyperemia	6 (6.0%)	Continuation of administration: 4 (after 1 month)
Eye pain	1 (1.0%)	Discontinuation of administration (after 1 month)
Iritis	1 (1.0%)	Discontinuation of administration (after 7 months)
Blepharitis	1 (1.0%)	Continuation of administration (after 7 months)

The total number of patients with adverse reactions was 9 (9.0%).

Twenty-one patients (21.0%) discontinued administration (Table 3). Of the patients with adverse reactions, one with conjunctival hyperemia discontinued omidenepag isopropyl administration after 1 week, and the symptom had disappeared. The other patients with conjunctival hyperemia switched to tafluprost after 2 weeks, and the symptom had disappeared. The patient with eye pain discontinued omidenepag isopropyl after 1 month, and the symptom has disappeared. Those with iritis switched to carteolol after 7 months, and inflammation was reduced. Other reasons for dropout in this study were additional medications for 4 patients (increased IOP in 2 and insufficient IOP-lowering effects in 2) and change of medications for 3 patients (insufficient IOP-lowering effects in 2 and progressed visual field defects in 1).

Table 3.

Dropout After Administration of Omidenepag Isopropyl

Dropout	No. of patients	Reasons: number
Interruption of visits	5 (5.0%)
Adverse reaction	4 (4.0%)	Conjunctival hyperemia: 2
		Eye pain: 1
		Iritis: 1
Added medications	4 (4.0%)	Increased IOP: 2
Added medications	4 (4.0%)	Insufficient IOP lowering effects: 2
Changed medication	3 (3.0%)	Insufficient IOP lowering effects: 2
Changed medication	3 (3.0%)	Progressed visual field defects: 1
Changed hospital	3 (3.0%)
Cataract surgery	2 (2.0%)

The total number of patients who dropped out was 21 (21.0%).

Of the patients who received additional eye drops, 1 had an increased IOP from 12 mmHg at baseline to 14 mmHg after 6 months, and timolol XE eye drop was introduced. In the other patient with increased IOP, the IOP was 16 mmHg at baseline and 19 mmHg after 6 months, and brimonidine was introduced. In 1 patient with insufficient IOP reduction, the IOP was 14 mmHg at baseline and 13 mmHg after 5 months, and a dorzolamide/timolol fixed combination was introduced. In the other patient with insufficient IOP reduction, the IOP was 19 mmHg at baseline and 18 mmHg after 4 months, and brimonidine was introduced.

Of the patients who switched their medications, the IOP in one with insufficient IOP reduction was 20 mmHg at baseline and after 2 months, and the patient was suspected to be a non-responder and was switched to carteolol. In the other patient who switched medications, the IOP was 13 mmHg at baseline and after 1 month, and the patient was suspected to be a non-responder and was switched to carteolol.

For the patient who experienced progression of visual field defects, the mean deviation value was −1.66 dB at baseline and −3.34 dB after 8 months of administration. This patient was switched to a latanoprost/carteolol fixed combination.

Discussion

Omidenepag isopropyl is a prostanoid receptor agonist that is selective for the EP2 receptor. It works on 2 aspects, the uveoscleral and trabecular outflows, thereby facilitating the outflow of the aqueous humor.¹⁴ The EP2 receptor is present in the ciliary body, trabecula, iris, cornea, conjunctiva, and retina. It has been reported that smooth muscles relax due to the receptor, and IOP decreases due to the effect on the extracellular matrix.¹⁵

IOP lowering is important in the drug treatment of glaucoma. As the reason for targeting only NTG in this study, it tends to have a stable baseline IOP and is thought to require a stronger IOP lowering effect than primary open-angle glaucoma, which has a relatively high baseline IOP and is easily lowered by medication. Furthermore, among the Japanese patients in this study, NTG is more common, and omidenepag isopropyl has fewer cosmetic adverse reactions¹⁶ than prostaglandin analogs, which are currently the first choice drugs.

In the patients in this study, IOP significantly decreased over 12 months after administration. The reduction in IOP observed was from 1.5 to 2.1 mmHg. In a phase-2 clinical trial conducted in the United States, omidenepag isopropyl was administered to patients with primary open-angle glaucoma or ocular hypertension for 4 weeks, and the diurnal variation of IOP was investigated.⁶ The IOP reductions and reduction rates from baseline at each time point on the final visit ranged from 6.8 to 7.9 mmHg and 27.5% to 32.0%, respectively. In a phase-2 clinical trial conducted in Japan, the IOP reductions and reduction rates from baseline at each time point on the final visit ranged from 5.1 to 5.2 mmHg and 21.4% to 21.8%, respectively.⁶ The IOPs at baseline in the clinical trials in the United States and Japan were 24.8 ± 1.7 mmHg and 23.8 ± 1.4 mmHg, respectively.

The clinical trial of omidenepag isopropyl conducted in Japan (the phase 3 AYAME study) reported the IOP-lowering efficacies and safety of omidenepag isopropyl and latanoprost over 4 weeks for primary open-angle glaucoma and ocular hypertension.⁷ The IOP reduction achieved with omidenepag isopropyl was found to be non-inferior to that achieved with latanoprost. The IOP before the administration of omidenepag isopropyl was 23.8 ± 1.7 mmHg, and the IOP reduction and reduction rate at 4 weeks after administration were 5.9 ± 0.2 mmHg and 24.9%, respectively. In the phase-3 RENGE study conducted in Japan, omidenepag isopropyl was administered to patients with primary open-angle glaucoma or NTG for 52 weeks.⁸

The patients were divided into 2 groups according to their baseline IOPs: Group 1 (16 – 22 mmHg) and Group 2 (22 – 34 mmHg). The IOPs at baseline in Groups 1 and 2 were 18.7 ± 1.7 mmHg and 24.1 ± 2.4 mmHg, respectively. The reductions in IOP after 52 weeks in Groups 1 and 2 were 3.7 ± 0.3 mmHg and 5.6 ± 0.5 mmHg, and the reduction rates were 19.5% ± 1.8% and 23.4% ± 1.9%, respectively. In this study, the IOP at baseline was lower than that recorded in the United States and Japanese clinical trials mentioned previously.^6–8 Therefore, the IOP-lowering effects were considered somewhat poor.

The efficacy of prostaglandin analogs for IOP lowering in patients with NTG for 12 months (1 year) or more has been reported in several studies (Table 4).^17–23 The IOP reductions and reduction rates reported in previous studies were 1.86 mmHg and 12.4%, and 2.4 mmHg and 16% for latanoprost^17,18; 2.11 mmHg and 14.6%, 2.71 mmHg and 18.3%, and 3.3 mmHg and 19.6% for travoprost^17,19,20; 2.20 mmHg and 14.0%, and 2.6 mmHg and 14.4% for tafluprost^17,21; and 4.1 mmHg and 24.3%, and 5.2 mmHg and 28.1% for bimatoprost, respectively.^22,23

Table 4.

Intraocular Pressure-Lowering Effects of Prostaglandin Analogs for Normal-Tension Glaucoma

Eye drops	References	No. of patients	Administration period	Pre-IOP (mmHg)	IOP reduction (mmHg)	IOP reduction rate (%)
Latanoprost	Oh and Park¹⁸	63	12 months	15.0 ± 2.7	2.4 ± 0.2	16
Latanoprost	Kim et al.¹⁷	59	60 months	14.98 ± 3.67	1.86 ± 2.95	12.4
Travoprost	Suh et al.¹⁹	45	12 months	14.79 ± 2.51	2.71 ± 3.90	18.3
	Inoue et al.²⁰	76	1 year	16.8 ± 2.6	3.3	19.6
	Kim et al.¹⁷	59	60 months	14.49 ± 2.74	2.11 ± 2.16	14.6
Tafluprost	Inoue et al.²¹	55	12 months	15.7 ± 2.2	2.6	14.4 ± 12.5
	Kim et al.¹⁷	59	60 months	15.69 ± 3.11	2.20 ± 2.64	14.0
Bimatoprost	Inoue et al.²²	62	12 months	16.7 ± 2.2	4.1	24.3 ± 11.3
Bimatoprost	Araie and Kitazawa.²³	40	52 weeks	18.5 ± 1.7	5.2 ± 1.7	28.1 ± 9.4
Omidenepag isopropyl	The current study	100	1 year	15.5 ± 2.7	1.6 ± 2.3	9.3 ± 13.8

The IOP lowering measured in the current study for omidenepag isopropyl (1.6 ± 2.3 mmHg and 9.3% ± 13.8%) was non-inferior to those reported previously for prostaglandin analogs. Omidenepag isopropyl maintains a good IOP-lowering efficacy in the long term in patients with NTG; this efficacy is comparable to that of prostaglandin analogs.

No severe adverse reactions were observed in the clinical trials conducted in Japan and the United States reported in 2019 and 2020.^6,7 In a phase-2 clinical trial in the United States, the adverse reactions observed in 14 patients were conjunctival hyperemia (14.3%), ocular hyperemia (14.3%), photophobia (14.3%), and eye pain (14.3%).⁶ In a clinical trial in Japan, adverse reactions in the 22 patients were conjunctival hyperemia (22.7%) and corneal thickening (9.1%).⁶ In a clinical trial (phase 3 AYAME study), conjunctival hyperemia was observed in 24.5% of patients, corneal thickening in 11.7%, eye pain in 4.3%, photophobia in 4.3%, adenoviral conjunctivitis in 3.2%, and others.⁷ Forty-two patients (49.4%) had adverse reactions with the single-agent administration of omidenepag isopropyl in the phase-3 RENGE study (Groups 1 and 2).

Of the 42 patients, 16 (18.8%) had conjunctival hyperemia, 5 (5.9%) had macular edema, and 5 (5.9%) had cystoid macular edema. Adverse reactions observed in the current study were conjunctival hyperemia in 6 (6.0%), eye pain in 1 (1.0%), iritis in 1 (1.0%), and blepharitis in 1 (1.0%). More patients participated in the current study than in the clinical trials, and the rate of adverse reactions may have been lower than that for the clinical trial. The frequency of conjunctival hyperemia was greater in the clinical trials. However, few patients complained of conjunctival hyperemia in this study; it is likely they were previously informed about it and expected it. The highest frequency of conjunctival hyperemia was the same as in the clinical trial.^6–8

There was no dropout in the clinical trials.^6,7 Nine patients (10.6%) dropped out due to adverse reactions with the single-agent administration of omidenepag isopropyl in the phase-3 RENGE study (Group 1 and Group 2).⁸ Of the 9 patients, 3 had macular edema, 2 had cystoid macular edema, 2 had cystoid macular edema and retinal detachment, and others. In the current study, 4.0% of the patients discontinued administration because of adverse reactions.

As the limitations of this study, discontinued administration due to the occurrence of adverse reactions was not standardized because it was done at the patient's request or physician's discretion. In addition, the evaluation of IOP was performed at the physician's discretion and was not standardized. Since some patients may show insufficient IOP-lowering effects due to non-responsiveness to omidenepag isopropyl, careful follow-up after administration is necessary.

Conclusions

Since omidenepag isopropyl is now available for use in Japan, we investigated its long-term efficacy and safety in patients with NTG. IOP significantly decreased after administration over 12 months. There was no difference in the visual field defects until 12 months after administration. Adverse reactions (conjunctival hyperemia, eye pain, iritis, or blepharitis) occurred in 9.0% of the patients. The long-term efficacy and safety of omidenepag isopropyl in patients with NTG are almost satisfactory. It is possible to use omidenepag isopropyl as the first-choice treatment for patients with NTG.

Footnotes

Author Disclosure Statement

K.I. reports grants from Teijin, Otsuka, and Wakamoto; lecture fees from Otsuka, HOYA, Pfizer, Senju, Santen, Allergan, Novartis, and Carl Zeiss Meditec; S.K.-S. reports lecture fees from Santen, Novartis, Alcon, AMO, Sucampo, Senju, Otsuka, Pfizer, and Kowa; N.N. reports grants from Wakamoto; K.S. reports lecture fees from Kowa and Novartis; K.I. reports lecture fees from Alcon, Pfizer, Santen, Senju, Otsuka, Kowa, Sucampo, GlaxoSmithKline, JFC Sales Plan, Japan Ophthalmic Instruments Association, Novartis, Wakamoto, Allergan, Bayer Yakuhin, and Nitto Medic; G.T. reports grants from Pfizer, Santen, Senju, Eisai, Handaya, Kowa, and Otsuka; lecture fees from Santen, Senju, Allergan Japan, and TOPCON. M.S. report no other conflicts of interest in this work.

Funding Information

No funding was received for this article.

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