Omidenepag Isopropyl 0.002% versus Latanoprost 0.005% in Open-Angle Glaucoma/Ocular Hypertension: The Randomized Phase III PEONY Trial

Introduction

Glaucoma is one of the leading causes of irreversible vision loss and blindness,¹ affecting more than 80 million people worldwide.² High intraocular pressure (IOP) is the primary risk factor and the only therapeutically modifiable factor for glaucoma. Lowering IOP has been shown to reduce the risk of developing glaucoma in high-risk ocular hypertensive patients³ and to reduce the risk of disease progression in patients with manifest glaucoma.^4,5

Topical medical therapy is a common first-line approach to glaucoma treatment, with prostaglandin analogues (PGAs) being the first choice of treatment owing to their superior efficacy and safety compared with other classes of drugs and their convenient once-daily dosing.^6,7 PGAs lower IOP by interacting with the prostaglandin F_2α receptors (FP receptors), activating a series of signaling pathways that upregulate the expression of matrix metalloproteinases, resulting in remodeling of the extracellular matrix of both the ciliary body and trabecular meshwork. This results in increased drainage of aqueous humor from the eye through the uveoscleral and, to a lesser extent, the trabecular outflow pathways.^6,7

The use of PGAs has several drawbacks, for example, their chronic use can lead to appearance-altering changes, also known as prostaglandin-associated periorbitopathy (PAP).⁸ PAP includes iris color changes and periorbital skin hyperpigmentation; vellus hair growth; eyelash changes including lengthening, thickening, and/or darkening; deepening of the upper eyelid sulcus (DUES), periorbital fat loss, ptosis, and in many cases enophthalmos.^7–14 The success rate of trabeculectomy at 24 months was found to be significantly lower in patients with than without DUES (P < 0.0001), suggesting that DUES can complicate ocular surgery due to eyelid changes and/or recession of the globe into the orbit.¹⁵

Omidenepag is a member of a new class of IOP-lowering drugs with non-prostaglandin structure, being a selective agonist of the prostanoid EP2 receptor.^16,17 Omidenepag is generated by hydrolysis of its prodrug omidenepag isopropyl (OMDI) by corneal esterases during ocular penetration.¹⁶ Omidenepag exhibits agonist activity with high affinity at EP2 receptors, but no binding activity at FP receptors, reducing IOP by increasing both uveoscleral and trabecular outflow.^16,17 Omidenepag does not inhibit adipogenesis and should not cause DUES.¹⁸ Additionally, a pre-clinical study in mice found that omidenepag did not cause eyelash changes.¹⁹ Clinical trials showed that IOP reduction by OMDI was comparable to that of latanoprost, with OMDI showing a notable absence of FP receptor-mediated side effects such as skin hyperpigmentation and lash changes.^20–23 OMDI ophthalmic solution 0.002% has been approved for the reduction of IOP in patients with glaucoma/primary open-angle glaucoma (OAG) or ocular hypertension (OHT) in Japan, India, Singapore, South Korea, Taiwan, Malaysia, the Philippines, Thailand, and the United States.^20,24,25

The Phase 3 PEONY trial was conducted in four Asian countries, India, Taiwan, Korea, and Singapore, to determine if the mean diurnal IOP reduction with OMDI ophthalmic solution 0.002% was non-inferior to that of latanoprost ophthalmic solution 0.005% (Xalatan^®, Pfizer) at month 3 in subjects with OAG or OHT. This trial also compared mean IOP at 9AM, 1PM, and 5PM after treatment for 1 week, 6 weeks, and 3 months in patients treated with OMDI and latanoprost, with non-inferiority of OMDI relative to latanoprost defined as an upper limit of the 95% confidence intervals (CIs) for the difference between OMDI and latanoprost of ≤1.5 mmHg at all nine time points and ≤1.0 mmHg at five or more of the nine time points (ie FDA non-inferiority requirements).²⁶

Materials and Methods

Study Design and Ethical Considerations

This phase 3, prospective, randomized, observer-masked, active-controlled, parallel-group, multinational, multicentre study (ClinicalTrials.gov identifier: NCT02981446) was conducted at 36 sites in Asia, including 13 in India, nine each in South Korea and Taiwan, and five in Singapore. The study was conducted in accordance with the tenets of the Declaration of Helsinki. The protocol was reviewed and approved by institutional ethics committees at each participating center (Supplementary Table 1), and all subjects provided written informed consent.

Participants

Subjects were eligible if they were aged ≥18 years and had OAG, including pigmentary or pseudoexfoliation components, or OHT in both eyes with IOP ≥22 mmHg and ≤34 mmHg at 9AM, 1PM, and 5PM after washout of any IOP-lowering medication or were treatment naive. Additional eligibility criteria in both eyes included best-corrected visual acuity (BCVA) of 0.6 logMAR (Snellen equivalent 20/80) or better, central corneal thickness (CCT) between 480 and 600 microns, and open anterior chamber angles of Shaffer grade ≥2. Subjects with childbearing potential were required to utilize an acceptable form of birth control during study participation.

Key exclusion criteria included advanced glaucoma (visual field mean deviation worse than −12 dB) in either eye, any prior glaucoma laser or incisional procedures intended to lower IOP, inability to safely wash out existing IOP-lowering agents, any ocular surgery or ocular laser treatment within 90 days prior to screening, corneal abnormalities precluding accurate IOP assessment (including prior keratorefractive surgery), or any ocular or systemic comorbidity precluding safe use of either agent or that might confound study results. The continued use of systemic medications known to affect IOP was permitted by the investigator if no changes in therapy were anticipated during study participation, except that treatment with corticosteroids by any route was prohibited.

Visits and Assessments

This 3-month study included five scheduled visits: screening, eligibility/baseline, and 1 week, 6 weeks and 3 months after initiating treatment. The screening visit included a comprehensive eye examination to determine preliminary eligibility, at which time washout of all IOP-lowering therapy (4 weeks for prostaglandin analogues, rho kinase inhibitors, beta-blockers, and alpha-1 antagonists; 3 weeks for alpha-2 agonists; 2 weeks for non-selective alpha agonists; and 1 week for miotics and topical/oral carbonic anhydrase inhibitors) was initiated. If not performed within 3 months prior to the screening visit, gonioscopy was performed at screening to assess the angle of the anterior chamber, with the Shaffer scale used to rate the degree of angle closure.

At the eligibility/baseline visit, IOP was assessed at 9AM, 1PM, and 5PM by Goldmann applanation tonometry using the described two-person operator/recorder protocol, with 2–3 measurements taken per time point.²⁷ Upon final confirmation of eligibility (IOP 22–34 mmHg at all three time points), participants were randomized 1:1 to one drop of OMDI 0.002% or latanoprost 0.005%, instilled once per day at 9PM, for 3 months. While on therapy, IOP was measured at three time points (9AM, 1PM, and 5PM) at 1 week, 6 weeks, and 3 months after randomization, with visual acuity and slit-lamp biomicroscopic examination performed immediately before and CCT measured immediately after measuring IOP at 9AM.

Changes in appearance, including of the iris, eyelash, and eyelid, were assessed by standardized photographic documentation of the eyes at baseline and evaluated at each on-treatment visit. Ophthalmoscopy was performed at baseline and exit visits.

Randomization and Masking

The study utilized a blocked randomization schedule, with a fixed block size stratified by baseline mean diurnal IOP in the study eye (<25 mmHg and ≥ 25 mmHg) and diagnosis (OAG or OHT). Randomization was conducted via an Interactive Web Response System. Subjects received a study medication kit numbered using the randomization schedule. Because the shape of the eyedrop bottles of the OMDI and latanoprost ophthalmic solutions were different, they were placed in identical kits. To maintain masking of the investigator and examiner during this study, study medications were dispensed and collected by authorized study staff other than the investigator or examiner. Subjects were instructed not to show or tell the investigator, examiner, or any other study subject about the eyedrop bottles. When the study medications were collected, the kits containing the used and unused eyedrop bottles were sealed.

Primary and Secondary Endpoints

The primary efficacy endpoint was mean diurnal IOP at month 3. A key secondary efficacy endpoint was mean IOP at each of the nine on-treatment time points. Other secondary efficacy endpoints included mean diurnal IOP at weeks 1 and 6 and the proportions of participants with mean diurnal IOP ≤18 mmHg and with mean diurnal IOP reductions from baseline of ≥20%, ≥25%, and ≥30% at weeks 1 and 6 and month 3. Safety endpoints included the nature and incidence of treatment-emergent ocular and systemic adverse events, BCVA, and ocular examination findings.

Statistical Analysis

Sample Size Calculation

Based on a between-group difference in mean diurnal IOP at month 3 of 0 mmHg, with a standard deviation of 4.0 mmHg, 151 subjects per group would provide 90% power to demonstrate the non-inferiority of OMDI compared with latanoprost (two-sided α = 0.05 and non-inferiority margin of 1.5 mmHg). Assuming a premature discontinuation rate of 16%, 360 subjects (180 per group) were scheduled to be randomized.

Other Statistical Analyses

Efficacy was analyzed in the full analysis set, consisting of all randomized subjects who received at least one dose of study medication and provided at least one on-treatment IOP measurement, as well as in the per protocol population, consisting of subjects in the full analysis set with no major protocol violations. One eye per subject was analyzed (the study eye): either the sole qualifying eye, the eye with the higher baseline mean diurnal IOP if both eyes qualified, or the right eye if the baseline mean diurnal IOP in the two eyes was equal. The primary endpoint was assessed using a mixed-effects model for repeated measures (MMRM), which included treatment, visit, diagnosis, country, and treatment–visit interaction as fixed effects, baseline mean diurnal IOP as a covariate, and subject as a random effect. Within-subject error was modeled using an unstructured covariance matrix. The least-squares (LS) means of the treatment response within each group and their differences (OMDI minus latanoprost) were reported with 95% CIs. Non-inferiority of OMDI relative to latanoprost was defined as an upper limit of the 95% CIs for the LS mean difference in mean diurnal IOP at month 3 of ≤1.5 mmHg. Mean IOP at each of the nine on-treatment time point (ie, 9AM, 1PM, and 5PM after treatment for 1 week, 6 weeks, and 3 months), was analyzed using a similar MMRM approach, with non-inferiority defined as an upper limit of the 95% CIs for the difference at all nine time points of ≤1.5 mmHg and at five or more of time points of ≤1.0 mmHg. If non-inferiority was demonstrated, a similar analysis was intended to test for the superiority of OMDI over latanoprost, with superiority defined as an upper limit of the 95% CI for the difference in mean diurnal IOP at week 1 of <0 mmHg. Safety was assessed in the safety population, defined as all randomized subjects who received at least one dose of study medication.

Results

Disposition and Demographics

A total of 370 subjects were randomized, 185 to each treatment, with all receiving at least one dose of study medication (Figure 1). One subject in the OMDI group was excluded due to having no on-treatment IOP measurements, ie, this subject never returned for follow-up visits after receiving the medication. Overall, 23 subjects did not complete the study: four in the OMDI group and two in the latanoprost group for adverse events (AEs); two in the OMDI group for protocol violations; eight in the OMDI and five in the latanoprost group who withdrew from the study; and one in each group for other reasons.

Figure 1 Patient Disposition.

Table 1 shows the baseline demographic and clinical characteristics of the 369 subjects in the full analysis set. Their mean (standard deviation) age was 53.6 (13.0) years, 52.6% were male, and 100% were Asian, with 54.5% enrolled at sites in India, followed by Taiwan (27.4%), Korea (11.1%) and Singapore (7.0%). Of these subjects, 64.5% had OAG and 33.1% had OHT; 46.9% were not using IOP-lowering medication during enrollment, 98.6% had brown eyes, and 90% were phakic. No clinically meaningful differences between treatment groups were observed.

Table 1 Demographic Characteristics of the Subjects in the Full Analysis Set (N = 369)

Primary Efficacy Endpoint

Figure 2 shows the mean diurnal IOP in each group at baseline and at each on-treatment visit. Baseline mean (standard error [SE]) diurnal IOPs were 24.6 (0.17) mmHg in the OMDI group and 24.5 (0.15) mmHg in the latanoprost group. At month 3, the LS mean (SE) diurnal IOPs were 17.5 (0.25) mmHg in the OMDI group (change from baseline −7.1 mmHg, 28.8%) and 16.8 (0.25) mmHg in the latanoprost group (change from baseline −7.8 mmHg, 31.3%), with a between-group difference in mean diurnal IOP of 0.6 mmHg (95% CI: 0.0–1.2 mmHg; p = 0.0366). Because the upper limit of the 95% CI between the two groups was ≤1.5 mmHg, OMDI was deemed non-inferior to latanoprost. This primary analysis was also supported by four prespecified non-inferiority sensitivity analyses: 1) MMRM analysis based on per-protocol population (PPP), in which the mean difference in mean diurnal IOP was 0.7 mmHg (95% CI: 0.1–1.3 mmHg; p = 0.0332); 2) analysis by ANCOVA based on FAS, in which the mean difference in mean diurnal IOP was 0.5 mmHg (95% CI: −0.0–1.1 mmHg; p = 0.0729); 3) analysis by ANCOVA based on PPP, in which the mean difference in mean diurnal IOP was 0.6 mmHg (95% CI: −0.0–1.2 mmHg; p = 0.0561); and 4) analysis by ANCOVA of completers, in which the mean difference in mean diurnal IOP was 0.7 mmHg (95% CI: 0.1–1.3 mmHg; p = 0.0213).

Figure 2 Baseline mean diurnal IOP and least-squares mean diurnal IOP ± standard error at each on-treatment study visit by treatment group.

Key Secondary Efficacy Endpoints

Figure 3 shows the mean (SE) IOP at each time point in both groups, measured at 9AM, 1PM, and 5PM during the baseline visit and after treatment for 1 week, 6 weeks, and 3 months. The LS mean IOPs across all 9 time points ranged from 17.2 to 19.0 mmHg in the OMDI group and from 16.7 to 18.8 mmHg in the latanoprost group; these represented mean IOP reductions from the baseline of −5.8 to −7.3 mmHg (23.5–29.5%) in the OMDI group and of −6.1 to −7.9 mmHg (24.3–31.7%) in the latanoprost group. Differences in mean IOP between the two groups ranged from −0.2 to +0.9 mmHg. The prespecified criteria for non-inferiority of OMDI to latanoprost were satisfied, in that the upper limit of 95% CIs of these differences in mean IOP were ≤1.5 mmHg at all nine time points and ≤1.0 mmHg at five of these nine time points, including all three time points at week 1 and 9AM at week 6 and month 3 (Table 2, Figure 4).

Table 2 Mean (SD) IOP at Baseline, Measured at 9AM, 1PM, and 5PM, and LS Mean (SE) IOP at 9AM, 1PM, and 5PM in Both Groups After Treatment for 1 Week, 6 Weeks, and 3 Months

Figure 3 Mean baseline and on-treatment IOP ± standard error at each study time point by treatment group.

Figure 4 Difference in least squares mean IOP between omidenepag isopropyl and latanoprost at each time point, showing that OMDI met the prespecified criteria for non-inferiority to latanoprost. That is, the upper limit of 95% CIs of these differences in mean IOP were ≤1.5 mmHg at all nine time points and ≤1.0 mmHg at five time points, including all three time points at week 1 and 9AM at week 6 and month 3.

Other Secondary Efficacy Endpoints

Mean diurnal IOPs at weeks 1 and 6 were also compared in the two groups. At week 1, the LS mean (SE) diurnal IOPs were 18.5 (0.26) mmHg (change from baseline −6.1 mmHg, 24.8%) in the OMDI group and 18.5 (0.27) mmHg (change from baseline −6.1 mmHg, 24.7%) in the latanoprost group, a difference of 0.0 mmHg (95% CI: −0.7, 0.7 mmHg; p = 0.9911). At week 6, the LS mean (SE) diurnal IOPs were 17.6 (0.25) mmHg (change from baseline −7.0 mmHg, 28.2%) in the OMDI group and 17.2 (0.25) mmHg (change from baseline −7.3 mmHg, 29.7%) in the latanoprost group, a difference of 0.4 mmHg (95% CI: −0.2, 1.0 mmHg; p = 0.2244). The comparison of mean diurnal IOP at week 1 was the efficacy endpoint for assessing the superiority of OMDI over latanoprost; superiority was not achieved (95% CI included 0, p > 0.05).

Table 3 shows the proportions of subjects in each treatment group achieving mean diurnal IOPs ≤18 mmHg and reductions from baseline of ≥20%, ≥25%, and ≥30%. In both treatment groups, the proportion of subjects achieving each endpoint increased slightly over time.

Table 3 Mean Diurnal IOP Outcomes at Week 1, Week 6 and Month 3 in Eyes Treated with Omidenepag Isopropyl (OMDI) and Latanoprost. The Percentages of Eyes Achieving Each Endpoint at Each Time Point are Shown

Safety

The rates of all AEs, ocular AEs, and ocular AEs associated with treatment were 40.0%, 36.8%, and 23.2%, respectively, in the OMDI group and 29.7%, 21.1%, and 11.9%, respectively, in the latanoprost group. Both treatments were generally safe and well tolerated, with Table 4 showing the types and incidence of ocular AEs. The most common ocular AE in both groups was conjunctival hyperemia, occurring in 11.9% of the subjects in the OMDI group and 5.4% of the subjects in the latanoprost group. Four patients in the OMDI group discontinued treatment due to AEs (one each with uveitis, iritis, photophobia and foreign body sensation); two patients in the latanoprost group also discontinued study medication due to AEs (one with headache and one with blurred vision plus eye pain). The patient that developed uveitis had mild anterior chamber inflammation in both eyes from day 12 to day 29, which resolved following discontinuation from OMDI on day 22 and betamethasone sodium phosphate treatment. The patient with iritis experienced mild iritis in both eyes from day 8 to day 17, which resolved without treatment following discontinuation from OMDI on day 8.

Table 4 Nature and Incidence of Ocular Adverse Events in the Safety Population (N = 370) in the Omidenepag Isopropyl (OMDI) and Latanoprost Groups

Four AEs (in 3 subjects) of appearance-altering changes (blepharal pigmentation, eyelash thickening, growth of eyelashes) related to the PGAs were reported in the latanoprost group only, with 2 of 3 patients treatment-naïve at baseline, as well as the other patient PGA treatment naïve.

Mean CCTs in both groups were within typical ranges (547 µm in the OMDI group and 540 µm in the latanoprost group) and mean (SD) changes in CCT at month 3 were 3.4 (18.1) µm in the OMDI group and −1.7 (15.5) µm in the latanoprost group. Four subjects (seven eyes) in the OMDI group showed an increase in CCT (>50 µm) during the study, with three eyes resolved (within 50 µm of baseline); at month 3, CCT change from baseline ranged from 25 to 65 µm. One subject (one eye) in the latanoprost group showed an increase in CCT (>50 µm) and returned to 37 µm by month 3. None of the eyes in the present study experienced a change in visual acuity from the baseline greater than 10 letters/0.2 logMAR. In addition, none of these eyes manifested corneal edema or other ocular symptoms. No serious ocular AEs occurred in either group.

Discussion

OMDI constitutes a new class of IOP-lowering agents,^16,17 with an efficacy similar to that of latanoprost in patients with OAG/OHT.²¹ OMDI acts by binding to the EP2 receptor, a G protein-coupled transmembrane receptor found in the ciliary body and trabecular meshwork, increasing both trabecular and uveoscleral outflow.^17,28 OMDI specifically stimulates the EP2 receptor but does not bind to other prostanoid receptors.¹⁶ The current trial compares OMDI to latanoprost, a standard first-line treatment and a PGA, the most effective existing class of glaucoma medication therapy.^29,30

This phase 3, multicenter, observer-masked, randomized, active-controlled clinical trial in subjects from four Asian countries, India, Taiwan, Korea, and Singapore, demonstrated that OMDI was non-inferior to latanoprost, as shown by mean diurnal IOP at Month 3 and by mean IOP at nine on-treatment time points, the US FDA IOP endpoint.²⁶ The reduction in mean diurnal IOP was comparable for OMDI (6.1–7.1 mmHg, 24.8–28.8%) and latanoprost (6.1–7.8 mmHg, 21.7–31.3%) during 3 months of once-daily dosing. The Safety profiles of the two drugs were comparable with low rates of AEs and treatment discontinuations due to AEs events. There were no serious ocular AEs in either group.

The efficacy outcomes reported in this study are consistent with prior reports. The phase 3 AYAME study compared OMDI 0.002% with latanoprost 0.005% each once daily in Japanese patients with POAG or OHT.²¹ The AYAME study was similar to the current study in that the comparator was latanoprost, the primary outcome was the change from baseline in mean diurnal IOP, and the analysis was designed to assess non-inferiority of OMDI compared with latanoprost. In the AYAME study, the baseline mean diurnal IOP was 23.8 mmHg in the OMDI group and 23.4 mmHg in the latanoprost group (slightly lower than the current study). The study demonstrated mean diurnal IOP reductions after 4 weeks of therapy of 5.9 mmHg and 6.6 mmHg, respectively, a treatment difference similar to that in the current study, confirming the non-inferiority of OMDI to latanoprost. Two Phase 2 studies in the United States with relatively small sample size (15–30 subjects per arm) reported mean diurnal IOP reductions with OMDI 0.002% of 7.4 mmHg at 4 weeks (from baseline 24.8 mmHg) and 5.5 mmHg at 3 months (from baseline 25.4 mmHg).²² Together, these studies show a consistent IOP-lowering effect of OMDI 0.002% across several ethnic populations including Asian, Japanese and US patients.

In this study the reduction in mean diurnal IOP was comparable for OMDI and latanoprost during 3 months of once-daily dosing. Similarly, when assessed across all nine on-treatment time points, the mean IOP reductions from baseline ranged from 5.8 to 7.3 mmHg (23.5–29.5%) in the OMDI group and 6.1–7.9 mmHg (24.3–31.7%) in the latanoprost group, indicating IOP control from morning (9AM) to afternoon (5PM). This magnitude of IOP reduction has been shown to reduce the risk of glaucoma progression^4,5 and is consistent with both the US and European glaucoma treatment guidelines for initial IOP reduction in eyes with mild-to-moderate OAG.^30,31

This study also found that OMDI was generally safe and well tolerated, at least in the short term. Common adverse events included conjunctival hyperemia, photophobia, and dry eye, consistent with previous reports.^20–24 Mean CCT was essentially unchanged (mean increase, 3.4 µm) through 3 months of OMDI treatment. Measured increases in CCT >50 µm were observed in four studies or fellow eyes in the OMDI group and one eye in the latanoprost group. At month 3 there were CCT increases in four eyes in the OMDI group, and none in the latanoprost group. The average CCT increase was subclinical, within the ranges of measurement variability and normal diurnal variation due to overnight corneal swelling,³² and manifested only as pachymetric measurements without any clinical signs or symptoms. These findings are consistent with past reports of subclinical increases in CCT during OMDI treatment, which were not associated with other safety variables including vision.^21–23 Endothelial cell density, which could be affected by the glaucoma disease process as well as by medical, laser, and surgical interventions for glaucoma,³³ was not assessed in this study. No cases of macular edema were observed in this study, although OCT was not planned in the study protocol, except in patients with diagnosed or suspected macular edema during the study. However, pseudophakia was observed in only 10.0% (37/369) of the study population, specifically 13.6% (25/184) in the OMDI group and 6.5% (12/185) in the latanoprost group. In a prior phase 3 long-term safety study conducted in Japanese patients, macular edema was observed only in pseudophakic eyes,²³ leading the Japanese regulatory authority to list pseudophakia as a contraindication to OMDI treatment.³⁴ Additional phase 3 studies have been performed in the US to further characterize the safety profile of OMDI.^35,36

Appearance-altering AEs, including periocular pigmentation and eyelash thickening, lengthening, and/or darkening, were observed in only a few latanoprost-treated subjects, underscoring likely differences in receptor activity, signal cascade, and mechanism of action of these two drugs. None of the subjects in the latanoprost group experienced DUES, which was not surprising as this was a short-term study, although latanoprost inhibits adipogenesis.¹⁸ However, OMDI, as an EP2 agonist, does not inhibit adipogenesis,¹⁸ and therefore DUES is not expected to develop in OMDI-treated eyes and has not been observed in studies of this drug including longer exposure.^20–24 Widespread use of PGAs for glaucoma may increase the incidence of appearance altering AEs or PAP.³⁷ Once-daily treatment with an agent having an efficacy similar to latanoprost, but with reduced incidence of PAP or appearance-altering effects on eyelids and lashes, may have potential value in the treatment of glaucoma.³⁸ Further studies of longer durations are necessary to confirm this finding.

This study had several advantages, including its being an observer-masked, randomized phase 3 clinical trial; its use of a common first-line glaucoma medication, latanoprost, as an active comparator that has proven IOP-lowering efficacy, and its large sample size with sufficient statistical power. Additionally, the study utilized primary and key secondary efficacy endpoints to satisfy both the US (mean IOP at nine individual time points) and global (mean diurnal IOP at the last visit) regulatory requirements. Even though both latanoprost and timolol are acceptable as the active control in Phase 3 registration trials per the FDA,²⁶ OMDI is the first US-approved ocular hypertensive agent, a new chemical entity, to successfully achieve non-inferiority to latanoprost with the FDA’s restrictive non-inferiority requirements.

The key limitation of the study was its relatively short duration of 3 months. Although this duration enabled adequate characterization of efficacy, it may not reveal safety issues associated with chronic exposure. Another limitation was its inclusion of only Asian subjects, including those from India, Taiwan, Korea, and Singapore, thus limiting the ability of the study results to be generalized to other ethnic/racial groups. However, phase 2 and 3 trials completed in the US and Japanese populations demonstrated similar IOP lowering efficacy and safety profiles.^20–24 Additionally, although no cases of macular edema were noted in this study, relatively few patients with pseudophakia were enrolled, and the treatment duration was only 3 months. Moreover, OCT was not planned in the study protocol, except in patients with diagnosed or suspected macular edema during the study. Additional phase 3 studies with longer durations are warranted to further characterize the drug profile in other populations that differ by race, iris color and eyelid color.

In summary, OMDI safely and effectively lowered IOP in Asian subjects with OAG or OHT, with mean diurnal IOP reductions and reductions at nine individual time points that were non-inferior to latanoprost over 3 months. The incidence of all AEs (including ocular AEs) was numerically higher with OMDI than with latanoprost. OMDI lowers IOP through interaction with the EP2 receptor, indicating that OMDI is a novel and safe option for the treatment of glaucoma.