Interim Results of Post-Marketing Observational Study of Omidenepag Isopropyl for Glaucoma and Ocular Hypertension in Japan

This multicenter, large-scale, post-marketing, non-interventional, prospective, observational study was conducted in Japan in accordance with the Good Post-Marketing Study Practice (MHLW Ordinance No. 171; December 20, 2004). The subject enrollment period was from December 21, 2018, to June 30, 2023. The entire study was scheduled for 7 years (November 27, 2018, to November 30, 2025), and is ongoing. The current interim analysis includes the data from patients retrieved until March 2021. The study was sponsored by Santen Pharmaceutical, the marketing authorization holder of OMDI in Japan. The study protocol was reviewed and approved by regulatory authorities; hence, an additional ethics review board approval was not mandated.

The target enrollment was 3900 patients. Patients with glaucoma and OH with no previous history of OMDI use were enrolled. The key exclusion criteria were patients with aphakic or pseudophakic eyes, and patients receiving tafluprost as a concomitant drug with OMDI, which was contraindicated. Patient enrollment was conducted using a central registration system to eliminate selection bias. All patients provided an oral or written informed consent. At the time of patient registration, the patients were classified under the monotherapy group or the concomitant therapy group, depending on whether or not other antiglaucoma drugs were used along with OMDI. Patients who started receiving OMDI as a monotherapy, but also started receiving other antiglaucoma/OH drugs during the study, were classified under the intermediate concomitant group. The data in the intermediate concomitant group were completely excluded from both monotherapy and concomitant therapy groups. For evaluation, monotherapy patients were further classified under the naïve monotherapy group when they never received any antiglaucoma therapy before starting OMDI and the switching monotherapy group when the current antiglaucoma treatment was switched to OMDI.

The observation period was 12 months after starting the administration of OMDI in both monotherapy and concomitant therapy patients. The data were collected using electronic case report forms (CRFs), which were submitted at 3 months, 7 months, and 12 months after its administration. The following data were non-interventionally collected from medical institutions: patient background, OMDI treatment status, concomitant medications used, IOP, corrected visual acuity, refraction (using spherical refraction), central corneal thickness; results from macular optical coherence tomography (OCT) examination, visual field test, objective assessment of conjunctival hyperemia, corneal fluorescein staining; and ADRs that occurred during OMDI administration. Each objective parameter was evaluated using a four-point score (0: none; 1: mild; 2: moderate; 3: severe).

An adverse event (AE) was defined as any untoward medical occurrences in a patient treated with OMDI, regardless of the causal relationship. If a doctor could not rule out the causality between AE and OMDI, the event was treated as an ADR. The aggregation of ADRs was performed using the MedDRA preferred terms. The objective findings and effectiveness analyses were based on the administration status of the evaluated eye. Only eyes with glaucoma or OH were assessed. If both eyes could be considered, the eye with a higher IOP value at the start of administration was assessed, and if the IOP of the left and right eyes was the same, the right eye was assessed. Patient-based tabulation was performed regardless of the evaluated eye.

The following fluctuations in ophthalmologic examination parameters (hereafter, parameter fluctuations) were noted regardless of each doctors' assessment: refractivity fluctuation, decrease or increase in refraction by ≥ 0.75 D compared to a previously measured value; central corneal thickness fluctuation, decrease or increase by ≥ 100 μm compared to a previously measured value; visual acuity fluctuation, previous deterioration of three or more lines of best-corrected visual acuity in Landolt C eye chart; IOP fluctuation, an increase by ≥ 50% compared to a previous measurement and the increased IOP was ≥ 20 mmHg; and visual field fluctuation, a decrease by ≥ − 6 dB compared to a previously measured value.

The incidence of parameter fluctuations was included as an ADR; however, incidence tables were separated from Table 4 (see below), which contains the ADRs reported by doctors.

The demographic and clinical characteristics of the study population are presented in Table 1. This study enrolled 1151 females (61.8%) and 711 males (38.2%), and the mean (±SD) age was 59.9 ± 13.0 years. Most of the study patients were diagnosed with NTG (1154 patients, 62.0%), followed by POAG (558 patients, 30.0%), PACG (30 patients, 1.6%), OH (87 patients, 4.7%), and others (33 patients, 1.8%). The mean IOP at baseline was 16.6 ± 4.5 mmHg. The baseline characteristics were similar between the groups except for the higher ratio of female patients (70.2%) in the switching monotherapy group than that in the naïve monotherapy (58.5%) and concomitant therapy groups (61.7%), and the higher mean Humphrey visual field MD (− 6.6 dB) and patient ratio of <  − 12 dB (21.3%) in the concomitant therapy group.

A total of 902 patients (48.4%) received OMDI as a naïve monotherapy, 342 patients (18.4%) switched to OMDI monotherapy from a prior treatment (switching monotherapy), 579 patients (31.1%) received OMDI concomitantly, and 39 patients (2.1%) received an intermediate concomitant therapy (Table 1). In the switching monotherapy group (342 patients), most patients received PGA (60.2%) before starting OMDI, followed by β-blockers (36.3%), CAIs (10.5%), α2 agonists (5.8%), and ROCK inhibitors (1.5%) (Table 2). In the concomitant therapy group (n = 579), most patients received β-blockers (74.4%), followed by CAIs (56.1%); only a few patients received PGAs (6.6%; Table 3). In total patients, the timing of receiving OMDI was at night in 85.5% and in the morning in 13.8%.

The overall incidence of ADRs was 24.3% (452/1862 patients).There was no significant difference of ADR incidence between the naïve monotherapy group (23.2%), switching monotherapy group (25.2%), and concomitant therapy group (25.6%). The most frequently reported ADRs were conjunctival hyperemia (3.6%), refractive disorders (3.1%), and myopia (1.1%) (Table 4). Four serious ADRs were reported in three patients: two cases had increased IOP, one had an iris synechiae, and one had a macular hole, and their causal relationships with OMDI were not ruled out. Currently, these ADR's outcomes were "improving". There were no observed ADRs categorized as PAP, such as eyelid pigmentation, eyelash abnormality, and deepening of the upper eyelid sulcus. In parameter fluctuations which were noted in regardless of each doctors' assessment, refractivity fluctuation (8.4%), and visual acuity fluctuation (2.0%) were the major fluctuations in all patients. There was no difference in parameter fluctuations between the monotherapy and concomitant therapy groups (Table 5). A total of 4 cases of macular edema including cystoid macular edema (0.2%) were observed; all had phakic eyes on both sides. These patients were aged 59, 60, 64 years and in her 60s; 3 were females. The onset of macular edema was 22, 31 52, and 190 days from the start of the OMDI treatment. In all patients, the condition was reported to be recovered or improved 31–111 days after the discontinuation of OMDI. In one patient, the shape of macular edema was reported as a cyst in inner retina without retinal detachment. It was considered to be moderate case. We could not identify any specific common background for these 4 patients. One patient had an epiretinal membrane and dry eye as concomitant ocular diseases. One patient had a concomitant lattice retinal degeneration and a history of retinal photocoagulation. One patient had a cataract, dry eye, and a history of trabeculectomy. The remaining patient had no concomitant disease or any disease history.

A conjunctival hyperemia score of ≥ 1 was observed in 9.5% of patients at baseline (n = 1774), 16.6% at 3 months and 8.3% at 12 months (Fig. 2). The mean conjunctival hyperemia score was 0.1 ± 0.4 at baseline, 0.2 ± 0.4 at 3 months, 0.1 ± 0.3 at 6 months, and 0.1 ± 0.3 at 123 months with statistical significance at 3 months (p < 0.05), but not at 6 or 12 months.

No statistically significant changes were observed in visual acuity (log value) score [0.022 ± 0.136 at baseline (n = 1660) to 0.018 ± 0.123 at 12 months (n = 216)].

The mean central corneal thickness was 539.8 ± 35.6 μm at baseline (n = 153) and 544.6 ± 34.9 μm at 12 months (n = 15), as measured by a pachymeter, and was 523.8 ± 42.3 μm at baseline (n = 222) and 535.4 ± 41.2 μm at 12 months (n = 22), as measured by specular microscopy. No statistically significant changes in refraction were observed between the baseline and at any time points.

The mean IOP for all patients was 16.6 ± 4.5 mmHg (n = 1836) at baseline. The mean IOP decreased significantly (p < 0.05) and was maintained around 14 mmHg stably throughout the study period. The mean change in IOP at 12 months was − 1.9 ± 2.9 mmHg, with − 10.4 ± 16.5% change from baseline (Fig. 3).

The mean IOP at baseline in the naïve monotherapy, switching monotherapy, and concomitant therapy groups were 17.0 ± 3.8 mmHg, 15.6 ± 3.7 mmHg, and 16.4 ± 5.8 mmHg, respectively. The mean IOP decreased significantly over 12 months, regardless of these treatment patterns (p < 0.05). The mean IOP change from the baseline to 12 months was − 2.7 ± 2.6 mmHg (− 15.1% ± 13.7%) in the naïve monotherapy group, − 1.1 ± 2.6 mmHg (− 4.9% ± 16.2%) in the switching monotherapy group, and − 1.6 ± 3.1 mmHg (− 8.5% ± 17.6%) in the concomitant therapy group (Fig. 4).

The mean baseline IOP of patients with POAG, NTG, and OH was 18.4 ± 5.0 mmHg, 15.1 ± 2.9 mmHg, and 22.2 ± 4.5 mmHg, respectively. In the 12-month observation period, the mean IOP of patients with POAG, NTG, and OH decreased by − 2.5 ± 3.2 mmHg (− 12.6% ± 17.4%), − 1.5 ± 2.4 mmHg (− 9.0% ± 15.3%), and − 2.3 ± 4.5 mmHg (− 9.5% ± 20.8%), respectively. The differences were statistically significant at all time points irrespective of the diagnosis (p < 0.05) (Fig. 5).

The overall persistence rate (95% CI) over the 12-month observation period was 82.4% (79.9 − 84.7%) (Fig. 6). The main reasons for treatment discontinuation were the occurrence of AEs (n = 129; 35.3%) and perceived insufficient therapeutic effect (n = 73; 20.0%).