Glaucoma is a progressive optic neuropathy characterized by morphologic optic nerve changes associated with retinal ganglion cell death and visual field loss.1 It has an estimated prevalence of 64.3 million people2 and is the second leading cause of blindness worldwide.3 The main aim of glaucoma therapy is to maintain patients’ visual function and to improve their quality of life at a sustainable cost.1 Elevated intraocular pressure (IOP) is an important risk factor for glaucoma and, to date, lowering IOP is the only treatment strategy shown to slow or cease structural and functional progression of the disease.4
Several classes of ocular hypotensive medications are available. Although the precise IOP-lowering mechanism of action differs between treatment classes, they all influence aqueous humor dynamics by reducing the production or increasing the outflow of aqueous humor.5 Prostanoid F receptor agonists (FP agonists) effectively lower IOP by enhancing uveoscleral aqueous humor outflow.5 They are generally recommended as a first-line treatment for ocular hypertension (OHT) or primary open-angle glaucoma (POAG) as they provide good efficacy, are usually well tolerated, and have good treatment adherence because of their once-daily dosing regimen.1,6,7 However, approximately 40% of patients with glaucoma receiving FP agonist monotherapy will require adjunctive treatment to adequately lower IOP,8 and patients experiencing little or no reduction in IOP with FP agonists may be required to switch to an alternative agent.6,9,10 In addition, although systemic side effects are rare, ocular and periocular adverse events (AEs; so called prostaglandin-associated periorbitopathy) frequently occur.11,12
Glaucoma is a chronic disease requiring long-term therapy, and it is most prevalent in older age groups who often have multiple comorbidities. Current treatment options can be associated with a significant patient burden13,14; therefore, there is a need for well-tolerated pharmacotherapies with a once-daily dosing regimen and novel mechanisms of action.
Omidenepag isopropyl is an investigational ocular hypotensive agent; its pharmacologically active metabolite, omidenepag, is a selective, non-prostaglandin, prostanoid E2 receptor 2 (EP2), agonist.7 In a study in ocular hypertensive monkeys, omidenepag isopropyl was shown to reduce IOP by a novel mechanism: increasing aqueous humor outflow via both the conventional and uveoscleral pathways.15 In phase 1, open-label, single-center study, omidenepag isopropyl was shown to be generally well tolerated and demonstrated good IOP-lowering effects in both Japanese and white healthy volunteers.16
The 3 randomized phase 2 studies presented herein evaluated the safety and efficacy of 7 concentrations of omidenepag isopropyl ophthalmic solution (0.0003% to 0.003%) in comparison with latanoprost and placebo in patients with POAG or OHT to determine the optimal dose for further investigation in a phase 3 clinical trial program.
MATERIALS AND METHODS
Three phase 2, randomized, masked, controlled, parallel-group, multicenter, dose-finding studies were conducted consecutively. Study 1 (NCT01868126) was conducted at 7 study centers in the United States, study 2 (NCT02179008) was conducted at 15 study centers in United States, and study 3 (NCT02623738) was conducted at 15 study centers in Japan. The studies were conducted in accordance with Good Clinical Practice and the Declaration of Helsinki, and the protocols were approved by the institutional review boards responsible for each participating institution. Written informed consent was obtained from all patients before enrollment in the study.
Patients were screened for eligibility before entering a washout period, where prior IOP-lowering medications were discontinued according to the following schedule: ≥4 weeks for β-adrenergic antagonists, rho kinase inhibitors, prostamides, and prostaglandin analogs; ≥2 weeks for α-agonists and sympathomimetics; ≥5 days for carbonic anhydrase inhibitors and parasympathomimetics; and ≥1 day for no prior medication. Following the washout period, patients were randomized to receive 1 of 7 concentrations of omidenepag isopropyl ophthalmic solution (0.0003%, 0.001%, 0.0012%, 0.0016%, 0.002%, 0.0025%, or 0.003%), latanoprost (0.005%), or placebo. For each treatment regimen, 1 drop was administered to both eyes once daily at approximately 08:00 PM (study 1 and 2) or 09:00 PM±1 hour (study 3) for 28 days (studies 1 and 3) or 90 days (study 2). Safety and efficacy evaluations were performed at visit 3 (week 1), visit 4 (week 2), and visit 5 (week 4). In study 2 only, additional evaluations were performed at visit 6 (month 2) and visit 7 (month 3). In studies 1 and 2, at baseline and at each subsequent study visit, IOP was measured at 08:00 AM±30 minutes, 10:00 AM±5 minutes, 12:00 PM±5 minutes, and 04:00 PM±5 minutes. In study 2, at baseline and visit 7 (day 91), an additional IOP measurement was conducted at 06:00 PM±5 minutes. In study 3, at baseline and at each subsequent study visit, IOP was measured at 09:00 AM±30 minutes, 01:00 PM±30 minutes, and 05:00 PM±30 minutes. IOP measurements were obtained using Goldmann applanation tonometry. The IOP values at each measurement timepoint were represented as the mean of 2 consecutive measurements. If the difference between the 2 measurements was ≥3 mm Hg, a third measurement was taken and the median was used. The evaluation of safety was based on assessment of AEs and ocular parameters, including slit-lamp biomicroscopy variables, ophthalmoscopy variables, ocular symptoms, corrected visual acuity, central corneal thickness (CCT; measured by pachymetry), pupil diameter, iris color, and eyelash and eyelid changes. Pachymetry was carried out at visit 1 (day of washout initiation), visit 2 (baseline), and at each subsequent study visit (with the exception of study 2, in which pachymetry was only performed at visits 1, 2, 5, 6, and 7).
Randomization and Masking
Studies 1 and 2 were observer masked because of the differences between the omidenepag isopropyl and latanoprost eye-drop bottles. However, investigators, examiners, and sponsor personnel involved in the conduct of the study were masked to the study treatment. An authorized unmasked study staff member, who was not the investigator or examiner, dispensed and collected the study medications and queried patients about dosing compliance. Patients were instructed not to show the eye-drop bottles to or discuss the medications with either the investigator, the examiner, or other study participants. The active control treatment (latanoprost) containers were over-labeled and packaged in the same secondary package (eg, cardboard carton) as the investigational treatment (omidenepag isopropyl). Study 3 was double masked; the patients, investigators, examiners, and sponsor personnel involved in the study were masked to the study medication. The study medication randomization manager checked the indistinguishability of the study medication at randomization and unmasking. Within each study, patients were randomized equally to each treatment group using the permuted block method: study 1, 4 concentrations of omidenepag isopropyl ophthalmic solution (0.0003%, 0.001%, 0.002%, and 0.003%), latanoprost 0.005% and placebo; study 2, 5 concentrations of omidenepag isopropyl (0.0012%, 0.0016%, 0.002%, 0.0025%, and 0.003%) and latanoprost 0.005%; and study 3, 2 concentrations of omidenepag isopropyl (0.002% and 0.0025%) and placebo.
Men or women aged 18 years or older (studies 1 and 2) or 20 years or older (study 3) were enrolled if they had: a diagnosis of POAG or OHT in both eyes; a corrected visual acuity +0.6 LogMAR or better (study 1 and 2) or +0.2 decimal visual acuity or better (study 3) in both eyes; anterior chamber angle grade ≥2 (shaffer scale) in both eyes; and CCT of 500 to 600 μm (study 1) or 480 to 600 μm (studies 2 and 3) in both eyes. In studies 1 and 2, following the washout period, patients with a baseline IOP of 22 to 35 mm Hg in at least 1 eye at the 08:00 AM measurement timepoint and in the same qualifying eye at each additional timepoint were randomized. In study 3, following the washout period, patients with an IOP of ≥22 mm Hg in at least 1 eye and ≤34 mm Hg in both eyes at all measurement timepoints were randomized. Exclusion criteria included: visual field depression that was severe or at risk for progression; any corneal abnormality or other condition potentially interfering with reliable Goldmann applanation tonometry; the presence of any active external ocular disease, inflammation, or infection of the eye or eyelids; the presence or history of macular edema; history of iritis, uveitis, retinal detachment, or diabetic retinopathy; current retinal disease at risk for progression; history of invasive surgery for glaucoma; history of ocular surgery within 90 days before the washout phase; the use of contact lenses from 1 week before treatment phase initiation and during the study; and change of any existing chronic therapy that could substantially affect IOP or study outcomes within 30 days before screening, or anticipated change of such therapy during the study. Women who were pregnant, nursing, or potentially pregnant were also excluded. For studies 1 and 2, additional exclusion criteria included a diagnosis of open-angle glaucoma or OHT owing to pseudoexfoliation, pigment dispersion, or other etiology known to be less responsive to conventional drug therapy; advanced glaucoma that would be at risk for progression during the washout period; a history of recurrent corneal erosion syndrome; lack of an intact posterior capsule; and the use of periocular or ocular steroids within 30 days before screening. Additional exclusion criteria for study 3 included a history of refractive keratotomy or severe eye injury.
Endpoints and Statistical Methods
The sample sizes of studies 1 and 2 were not based on statistical considerations. Study power was determined using a standardized effect size δ/σ, where δ is the mean difference in the primary efficacy endpoint between an omidenepag isopropyl group and the comparator and σ is the common SD. In study 1, based on a 2-sided 2-sample t test it was determined that a sample size of 15 patients per group would provide ~75% power to detect a standardized effect size of 1 mm Hg. In study 2, based on a 1-sided 2-sample t test, it was determined that a sample size of 30 patients per group would provide ~80% power to detect a standardized effect size of 0.67 mm Hg (assuming a mean difference of 2 mm Hg and SD of 3 mm Hg). In study 3, based on the SD of a pooled analysis of placebo and omidenepag isopropyl 0.002% and 0.0025% groups from studies 1 and 2 (3.0 mm Hg), it was determined that a sample size of 16 patients per group would be required for 90% power to demonstrate superiority of omidenepag isopropyl to placebo. Therefore, assuming a 20% drop-out rate, a total of 60 randomized patients (20 patients per group) was established.
Efficacy analyses were based on the study eye of the full analysis set, comprising patients who met inclusion criteria, received ≥1 instillation of study drug, and had baseline and at least 1 postbaseline IOP measurement in the study eye. The study eye was defined as the eye with the higher mean diurnal IOP at baseline. If both eyes had the same mean diurnal IOP, the right eye was designated as the study eye.
The coprimary efficacy endpoints for study 1 and 2 were the observed IOP at each scheduled timepoint on the final study visit and the observed mean diurnal IOP on the final study visit. Secondary endpoints included the change from baseline in IOP at each scheduled assessment timepoint and change from baseline in mean diurnal IOP at each study visit. The primary and secondary efficacy endpoints were analyzed using descriptive statistics.
The primary efficacy endpoint for study 3 was the change in mean diurnal IOP from visit 2 (baseline) to visit 5 (week 4). Secondary endpoints included the change in mean diurnal IOP at each study visit; the change in IOP at each scheduled assessment timepoint; and the percentage of responders (percent reduction from baseline in diurnal IOP: ≥20%, ≥25%, ≥30%) at week 4. The least-squares mean (95% confidence interval) change in diurnal IOP was compared between each omidenepag isopropyl treatment group and the placebo group, with a mixed-effects model for repeated measures (MMRM), which used treatment group, visit, and interaction between treatment group and visit as fixed effects, baseline IOP as a covariate, and patient as a random effect. Secondary endpoints were analyzed by MMRM in the same manner as the primary efficacy endpoint. Adjusted P-values based on the Hochberg method for comparisons were determined between omidenepag isopropyl treatment groups and the placebo group.
Safety analyses were based on the safety analysis set, which comprised all patients who had received at least 1 instillation of study drug and for whom any safety information was available.
Patient Disposition, Demographics, and Baseline Characteristics
Studies 1, 2, and 3 took place between May 2013 and August 2013, June 2014 and January 2015, and December 2015 and February 2017, respectively. A total of 338 patients were randomized (study 1, N=91; study 2, N=184; study 3, N=63) and 337 were included in the safety analysis set and full analysis set. One patient in study 2 did not have any postbaseline IOP measurements; therefore, this patient was excluded from the analyses. Overall, 13 patients prematurely discontinued treatment after randomization because of AEs (n=6), lack of efficacy (n=4), protocol deviation (n=1), patient withdrawal (n=1), and loss to follow-up (n=1) (Fig. 1). Within each study, no clinically relevant between-group differences in demographics and baseline characteristics were identified. The patient populations in studies 1 and 2 were predominantly white, whereas those included in study 3 were all Japanese. The mean baseline IOP was also lower in study 3 compared with studies 1 and 2 (Table 1). Treatment compliance rates and dosing adherence determinations were high (≥75%) and similar across all treatment groups.
The mean observed IOP and IOP change from baseline at each assessment timepoint on the final study visit are presented in Table 2. In study 1, at week 4, the observed mean diurnal IOP scores in all active treatment groups were lower than that of the placebo group. The 0.002% concentration of omidenepag isopropyl demonstrated the lowest mean±SD diurnal IOP among the 4 concentrations evaluated (17.36±1.9 mm Hg in the omidenepag isopropyl 0.002% group, and 21.44±3.9 mm Hg, 20.21±2.8 mm Hg and 19.77±3.0 mm Hg in the 0.0003%, 0.001%, and 0.003% omidenepag isopropyl groups, respectively) and resulted in a lower mean±SD diurnal IOP compared with latanoprost 0.005% (17.7±2.1 mm Hg). Secondary efficacy analyses demonstrated that of the 4 omidenepag isopropyl doses evaluated, 0.002% resulted in the greatest reduction in mean diurnal IOP from baseline at all study visits. In addition, numerically, omidenepag isopropyl 0.002% performed similarly in IOP reduction to latanoprost 0.005% (Fig. 2A).
As omidenepag isopropyl, 0.002% achieved the greatest IOP reduction of the omidenepag isopropyl concentrations evaluated in study 1, additional concentrations of around 0.002% were investigated in study 2. At the final study visit (month 3), latanoprost 0.005% resulted in the greatest mean IOP reduction from baseline, followed by omidenepag isopropyl 0.0025% at all assessment timepoints except the 12:00 PM and 06:00 PM timepoints when omidenepag isopropyl 0.002% and 0.0025% demonstrated the greatest reductions, respectively (Table 2). At month 3, mean±SD diurnal IOP was lowest in the latanoprost 0.005% group (18.58±2.6 mm Hg), followed by omidenepag isopropyl 0.003% (19.26±3.4 mm Hg), 0.0025% (19.67±3.0 mm Hg), 0.002% (19.73±3.6 mm Hg), 0.0016% (20.69±4.3 mm Hg), and 0.0012% (20.86±3.1 mm Hg). Secondary efficacy analyses demonstrated that omidenepag isopropyl 0.003% and 0.0025% resulted in greater mean diurnal IOP changes from baseline at week 1 and week 2 compared with those of latanoprost 0.005% (Fig. 2B). At months 1, 2, and 3, latanoprost 0.005% resulted in the greatest reduction in mean diurnal IOP (Fig. 2B).
A typical dose-response relationship was observed from the lowest omidenepag isopropyl concentration evaluated (0.0003%) to the 0.002% concentration in study 1, and from 0.0012% to 0.0025% in study 2. The highest concentration evaluated, 0.003%, did not consistently produce the greatest IOP-lowering effects across all measurement timepoints in both studies 1 and 2.
Study 3 further evaluated the omidenepag isopropyl concentrations 0.002% and 0.0025% compared with placebo in Japanese patients. The primary efficacy analysis demonstrated that both concentrations resulted in significantly greater reductions in mean diurnal IOP from baseline to week 4 compared with placebo (P=0.0025 and P=0.0031 for omidenepag isopropyl 0.002% and 0.0025%, respectively) (Fig. 2C). Compared with placebo, both concentrations also resulted in significant reductions in mean diurnal IOP from baseline at week 1 (0.002%, P=0.0003; 0.0025%, P=0.0004), week 2 (0.002%, P=0.0067; 0.0025%, P=0.0025) (Fig. 2C), and at each scheduled assessment timepoint (all P<0.05) with the exception of the 09:00 AM timepoint at week 2 in the 0.002% group (Table 2). The 20%, 25%, and 30% responder rates (corresponding to a ≥20%, ≥25%, and ≥30% reduction from baseline in mean diurnal IOP) are shown in Figure 3. Omidenepag isopropyl 0.002% demonstrated significantly greater responder rates than placebo at all visits (all P<0.05) and numerically greater responder rates than the 0.0025% concentration.
The AEs reported in each study are summarized in Table 3. Three serious AEs were reported by 3 patients in study 2; all were nonocular and considered unrelated to study treatment (decreased blood potassium with an associated loss of consciousness and fall, hernia, and fall resulting in a tibia fracture requiring surgery occurring in the omidenepag isopropyl 0.002%, 0.0025%, and 0.003% groups, respectively). The most frequently reported AE was conjunctival hyperemia (<33%), the frequency of which increased with increasing omidenepag isopropyl dose. Other frequently reported AEs included photophobia and eye pain. All ocular AEs were mild or moderate in severity except for 1 case of severe photophobia reported in 1 patient receiving omidenepag isopropyl 0.003% in study 2. Most ocular AEs were considered causally related to study drug. Nonocular AEs were less frequently reported; most were considered unrelated to study medication. One report of headache (omidenepag isopropyl 0.0016%) and one of increased white blood cell count (omidenepag isopropyl 0.002% group) were considered possibly related to the study drug.
Six patients discontinued study participation because of ocular AEs including (1) mild blurred vision (omidenepag isopropyl 0.002% group); (2) mild iritis, moderate ocular pain, and moderate photophobia (omidenepag isopropyl 0.0012% group); (3) mild iritis, moderate ocular pain, and severe photophobia (omidenepag isopropyl 0.003% group); (4) moderate increased IOP (omidenepag isopropyl 0.003%); (5) moderate allergic conjunctivitis and moderate conjunctivitis bacterial (omidenepag isopropyl 0.0012% group); and (6) moderate conjunctival hyperemia, foreign body sensation, and burning/stinging (omidenepag isopropyl 0.0025% group). All ocular AEs leading to discontinuation resolved following study drug withdrawal. The 2 cases of mild iritis, presenting with anterior chamber cell, occurred 3 and 5 days following study drug initiation and recovered in 8 and 10 days, respectively, following study drug discontinuation without intervention.
Small mean increases in CCT (study eye) were observed with omidenepag isopropyl in all studies (Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/IJG/A236). No associated corneal edema findings were reported using biomicroscopy and no impact on visual acuity or IOP was detected.
No additional safety issues were identified based on an analysis of change from baseline to any posttherapy visit for the ocular safety parameters evaluated.
All evaluated doses of omidenepag isopropyl (0.0003% to 0.003%) demonstrated IOP-lowering effects in patients with POAG or OHT with once-daily dosing. Maximum IOP reductions were achieved as early as week 1, demonstrating an early onset of action; these reductions were maintained for up to 3 months.
A typical positive dose-response relationship was observed from the lowest omidenepag isopropyl concentration evaluated (0.0003%) to the 0.002% concentration in study 1, and from 0.0012% to 0.0025% in study 2. The highest concentration evaluated, 0.003%, did not consistently produce the greatest IOP-lowering effects across all measurement timepoints in both studies 1 and 2. Similarly, a lack of increased effect at the highest concentrations evaluated has also been seen in dose-ranging studies of other ocular hypotensive agents.17,18 The 2 most effective omidenepag isopropyl doses from studies 1 and 2 were further evaluated in study 3. In this study, the IOP-lowering effect of omidenepag isopropyl 0.002% was slightly greater than that of the 0.0025% concentration at all visits except for week 2. These data suggest that there is a plateau in the dose-efficacy response at approximately 0.002%. Omidenepag isopropyl doses of 0.002% and 0.0025% demonstrated clinically relevant IOP-lowering effects that were significantly greater than those of placebo, numerically greater than those of omidenepag isopropyl 0.003%, and similar to the effects achieved with latanoprost 0.005%. The IOP reductions achieved with omidenepag isopropyl 0.002% and 0.0025% in these studies are in the range observed in previous clinical trials with FP agonists in patients with POAG or OHT.19–22
Reductions in IOP achieved with omidenepag isopropyl 0.002% and 0.0025% reported in study 3 were lower than those reported in studies 1 and 2. This is likely because of differences in patient baseline characteristics. Previous studies have demonstrated that higher baseline IOPs are significantly associated with greater mean IOP reductions.23 Study 3 participants had a lower mean baseline IOP compared with those of studies 1 and 2. This was to be expected as study 3 was conducted in Japanese patients who typically have lower IOP values compared with white populations.24
Patients receiving omidenepag isopropyl 0.002% and 0.0025% experienced stable IOP-lowering effects at all scheduled assessment timepoints, supporting once-daily dosing. This observed IOP reduction is reported because of EP2 stimulation by omidenepag leading to an increase in aqueous humor outflow through both trabecular meshwork and uveoscleral routes, and consequently, IOP-lowering efficacy.15
All doses of omidenepag isopropyl investigated demonstrated an acceptable tolerability profile. Conjunctival hyperemia, a well-recognized side effect of hypotensive glaucoma treatment,25 was the most frequently reported AE in the combined omidenepag isopropyl groups; the incidence of this increased in a dose-dependent manner. As with the other reported ocular AEs, most cases of conjunctival hyperemia were mild in severity. The safety profiles of omidenepag isopropyl 0.002% and 0.0025% were similar with a slightly lower incidence of AEs in the 0.002% concentration group based on pooled data from studies 2 and 3.
Small mean increases in CCT (<24 μm) were observed in the omidenepag isopropyl groups. These CCT increases were similar to those observed with another EP2 receptor agonist;26 the extent of this change is within the range of normal diurnal variation (3% to 8% overnight corneal swelling).27 In studies 1 and 3, in which pachymetry was performed at every study visit, the increases in CCT did not increase substantially beyond week 2. In study 2, in which pachymetry was performed at week 4, month 2 and month 3, the increases in CCT seemed to plateau around month 2. It seems that there were slight numerical differences in CCT changes between studies 1 and 2 compared with study 3. This could be because of the different study populations enrolled; the patient populations in studies 1 and 2 were predominantly white, whereas those included in study 3 were all Japanese. However, the difference is negligible and is not considered to be clinically significant. In addition, the changes in CCT observed in these studies did not seem to be dose-dependent and were not associated with any safety concerns, for example, there were no reports of corneal edema in the biomicroscopy findings, and no impact on visual acuity or IOP. The impact of the CCT increase on corneal endothelial cell count will be investigated in a long-term study.
Key strengths of these randomized, multicenter, dose-finding studies include the use of both placebo and active comparator and the varied patient demographics. Superiority in IOP lowering compared with placebo demonstrated the assay sensitivity and showed that omidenepag isopropyl (0.002% and 0.0025%) was an effective IOP-lowering treatment. The studies were conducted in 2 distinct patient populations: one of Japanese patients and the other predominantly white. This increases the validity and generalizability of the results. In addition, in studies 1 and 2, the IOP reductions achieved with latanoprost 0.005% were comparable with previous clinical trial experience in a variety of patient populations with POAG or OHT,20–22 validating the study design and further demonstrating the extrapolation of these results to other study populations. Although studies 1 and 2 were observer masked only, procedures were in place to minimize bias. For example, investigators, examiners, and sponsor personnel involved in the conduct of the studies were masked to the study treatment; an authorized unmasked study staff member who was not the investigator or examiner dispensed and collected the study medication; patients were instructed not to show or discuss the eye drops with the investigator, examiner, or other study participants; and the active control treatment containers were over-labeled and packaged in the same secondary package as the investigational treatment (omidenepag isopropyl). One potential limitation is the small sample size in each treatment group, which is a common limitation in phase 2 dose-ranging studies. In addition, these studies did not include patients with glaucoma resulting from pseudoexfoliation, pigment dispersion, or other etiologies known to be less responsive to conventional drug therapies. This is typical for dose-ranging studies, where subtle differences in efficacy can be differentiated in responsive patients, leading to optimal dose determination. However, patients with exfoliative and pigmentary glaucoma were included in subsequent phase 3 trials.
In conclusion, of the omidenepag isopropyl doses evaluated, the 0.002% and 0.0025% doses demonstrated the greatest IOP-lowering effects, which were similar to those of latanoprost 0.005%. Both doses were well tolerated; however, as glaucoma is a chronic disease requiring long-term ocular hypotensive medication use to control IOP, it is preferable to expose patients to the lowest effective dose. Therefore, omidenepag isopropyl 0.002% was identified as the optimal dose for further investigation in a phase 3 clinical trial program.
Medical writing was provided by Alex Yardley, BSc, Helios Medical Communications, Cheshire, UK, which was funded by Santen. The study was sponsored by Santen.
1. European Glaucoma Society (EGS). Terminology and guidelines for glaucoma, 4th edition – Part 1. Br J Ophthalmol. 2017;101:1–72.
2. Tham Y-C, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040. Ophthalmology. 2014;121:2081–2090.
3. Quigley H, Broman A. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–267.
4. Mantravadi AV, Vadhar N. Glaucoma. Prim Care Clin Office Pract. 2015;42:437–449.
5. Schmidl D, Schmetterer L, Garhöfer G, et al. Pharmacotherapy of glaucoma. J Ocul Pharmacol Ther. 2015;31:63–77.
6. Prum BE, Rosenberg LF, Gedde SJ, et al. Primary open-angle glaucoma
preferred practice pattern®
guidelines. Ophthalmology. 2016;123:41–111.
7. Kirihara T, Taniguchi T, Yamamura K, et al. Pharmacologic characterization of omidenepag isopropyl
, a novel selective EP2 receptor agonist
, as an ocular hypotensive agent. Invest Ophthalmol Vis Sci. 2018;59:145–153.
8. Schmier JK, Lau EC, Covert DW. Two-year treatment patterns and costs in glaucoma patients initiating treatment with prostaglandin analogs. Clin Ophthalmol. 2010;4:1137–1143.
9. Inoue K, Setogawa A, Tomita G. Nonresponders to prostaglandin analogs among normal-tension glaucoma patients. J Ocul Pharmacol Ther. 2016;32:90–96.
10. Brennan N, Dehabadi MH, Nair S, et al. Efficacy and safety of bimatoprost in glaucoma and ocular hypertension
in non-responder patients. Int J Ophthalmol. 2017;10:1251–1254.
11. Inoue K, Shiokawa M, Higa R, et al. Adverse periocular reactions to five types of prostaglandin analogs. Eye (Lond). 2012;26:1465–1472.
12. Honrubia F, García-Sánchez J, Polo V, et al. Conjunctival hyperaemia with the use of latanoprost versus other prostaglandin analogues in patients with ocular hypertension
or glaucoma: a meta-analysis of randomised clinical trials. Br J Ophthalmol. 2009;93:316–321.
13. Kerr NM, Patel HY, Chew SS, et al. Patient satisfaction with topical ocular hypotensives. Clin Exp Ophthalmol. 2013;41:27–35.
14. Skalicky SE, Goldberg I, McCluskey P. Ocular surface disease and quality of life in patients with glaucoma. Am J Ophthalmol. 2012;153:1–9.
15. Fuwa M, Toris C, Fan S, et al. Effects of a novel selective EP2 receptor agonist
, omidenepag isopropyl
, on aqueous humor dynamics in laser-induced ocular hypertensive monkeys. J Ocul Pharmacol Ther. 2018;34:531–537.
16. Aihara M, Lu F, Kawata H, et al. Pharmacokinetics, safety and IOP lowering profiles of omidenepag isopropyl
, a selective EP2 agonist in healthy Japanese and Caucasian volunteers (Phase I study). Invest Ophthalmol Vis Sci. 2017;58:2104 (Abstract).
17. Eveleth D, Starita C, Tressler C. A 4-week, dose-ranging study comparing the efficacy, safety and tolerability of latanoprost 75, 100 and 125 μg/mL to latanoprost 50 μg/mL (Xalatan) in the treatment of primary open-angle glaucoma
and ocular hypertension
. BMC Ophthalmol. 2012;12:9.
18. Katz LJ, Cohen JS, Batoosingh AL, et al. Twelve-month, randomized, controlled trial of bimatoprost 0.01%, 0.0125%, and 0.03% in patients with glaucoma or ocular hypertension
. Am J Ophthalmol. 2010;149:661–671.
19. Cantor LB, Hoop J, Morgan L, et al. Bimatoprost-Travoprost Study Group. Intraocular pressure-lowering efficacy of bimatoprost 0.03% and travoprost 0.004% in patients with glaucoma or ocular hypertension
. Br J Ophthalmol. 2006;90:1370–1373.
20. Chen R, Yang K, Zheng Z, et al. Meta-analysis of the efficacy and safety of latanoprost monotherapy in patients with angle-closure glaucoma. J Glaucoma. 2016;25:e134–e144.
21. DuBiner H, Cooke D, Dirks M, et al. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol. 2001;45 (suppl 4):S353–S360.
22. Mishra D, Sinha BP, Kumar MS. Comparing the efficacy of latanoprost (0.005%), bimatoprost (0.03%), travoprost (0.004%), and timolol (0.5%) in the treatment of primary open angle glaucoma. Korean J Ophthalmol. 2014;28:399–407.
23. Hedman K, Alm A. A pooled-data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. Eur J Ophthalmol. 2000;10:95–104.
24. Choquet H, Thai KK, Yin J, et al. A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure. Nat Commun. 2017;8:2108.
25. Alm A, Grierson I, Shields MB. Side effects associated with prostaglandin analog therapy. Surv Ophthalmol. 2008;53(suppl 1):S93–S105.
26. Schachar RA, Raber S, Courtney R, et al. A Phase 2, randomized, dose-response trial of taprenepag isopropyl (PF-04217329) versus latanoprost 0.005% in open-angle glaucoma and ocular hypertension
. Curr Eye Res. 2011;36:809–817.
27. Feng Y, Varikooty J, Simpson TL. Diurnal variation of corneal and corneal epithelial thickness measured using optical coherence tomography. Cornea. 2001;20:480–483.