Twelve-month efficacy and safety of omidenepag isopropyl, a selective EP2 agonist, in open-angle glaucoma and ocular hypertension: the RENGE study.

PURPOSE: To assess the long-term safety and efficacy of omidenepag isopropyl (OMDI) 0.002% (a first-in-class, selective, non-prostaglandin, prostanoid EP2 receptor agonist), alone or administered concomitantly with timolol 0.5%, in patients with open-angle glaucoma (OAG, including normal-tension and exfoliation glaucoma) or ocular hypertension (OHT). STUDY DESIGN: Open-label, multicenter, Phase 3 study (NCT02822729). METHODS: Patients aged ≥ 20 years, with OAG or OHT, and a baseline diurnal intraocular pressure (IOP) ≥ 16- < 22 mmHg (Group 1) or ≥ 22- ≤ 34 mmHg (Groups 2 and 3) were enrolled. All patients (N = 125) received OMDI 0.002% once daily. Group 3 also received timolol 0.5% twice daily. IOP was measured at baseline and at Weeks 2, 4, 8, 12, 26, 40, and 52. RESULTS: Significant reductions in mean diurnal IOP from baseline occurred at every visit (P < 0.0001). Mean ± SE diurnal IOP reduction at Week 52 was -3.7 ± 0.3 mmHg (Group 1), -5.6 ± 0.5 mmHg (Group 2), and -8.4 ± 0.6 mmHg (Group 3). Most adverse events (AEs) were mild, and no serious treatment-related AEs were reported. Conjunctival hyperemia (incidence: monotherapy [Groups 1 and 2], 18.8%; concomitant [Group 3], 45.0%) and macular edema (ME)/cystoid macular edema (CME) (incidence: monotherapy, 11.8%; concomitant, 15.0%) occurred most frequently. All treatment-related ME/CME cases occurred in pseudophakic eyes and responded to standard-of-care treatment and study drug discontinuation. CONCLUSIONS: In this study, OMDI 0.002%, alone or administered concomitantly with timolol 0.5%, resulted in sustained IOP reduction over 52 weeks in patients with OAG or OHT. Concomitant treatment resulted in increased efficacy and increased incidence of conjunctival hyperemia.

Spatial and Temporal Relationship between Structural Progression and Disc Hemorrhage in Glaucoma in a 3-Year Prospective Study.

PURPOSE: To investigate the spatial and temporal relationship between disc hemorrhage (DH) and structural progression in patients with primary open-angle glaucoma (POAG) in a 3-year prospective study. DESIGN: Prospective cohort study. PARTICIPANTS: Patients with POAG and intraocular pressure of ≤18 mmHg on monotherapy with prostaglandin analogs. METHODS: Fundus photographs were taken at baseline and every 3 months for 3 years. Disc hemorrhage and structural progression were detected independently by flicker chronoscopy. If present, clock-hour disc locations in the right eye format and colocalization were determined. Statistical comparisons were based on mixed-effects models accounting for the correlation between different disc sites within the same eye and between fellow eyes in the same patient. MAIN OUTCOME MEASURES: Relationship between DH and structural progression at the same site. RESULTS: Among 195 eyes of 115 patients, DH appeared in 85 sites in 65 eyes (33.3%) and was most frequently at the 7 o'clock disc location (29.4%, P < 0.0001). Structural progression occurred at 63 sites of 52 eyes (26.7%) comparably in both superior and inferior hemidiscs, which was mostly detected as widening of the retinal nerve fiber layer defects (RNFLDs). Temporal RNFLD widening was common, whereas nasal widening occurred exclusively in the vertical quadrants (P = 0.035). Of 41 progression sites in eyes with DH, 28 sites (68.2%) had both DH and progression. Progression sites with DH were less common in the superior quadrant than in the inferior and temporal quadrants (P = 0.011). Eyes with DH had a significantly higher risk of progression than eyes without DH (hazard ratio, 3.72; P < 0.0001). For 63 progression sites, DH recurrence and more visits with DH at the progression site were significantly associated with shorter time to progression from baseline (P = 0.021, P = 0.017, respectively), whereas colocalization of DH and progression were not. CONCLUSIONS: In a 3-year prospective study with a Japanese POAG cohort, the relationship between DH and RNFLD and the pattern of RNFLD progression differed by disc location. The association between more frequent DH at the progression site and shorter time to progression indicates that DH may reflect vulnerability to same-site structural deterioration.

Intraocular pressure-lowering effect of omidenepag isopropyl in latanoprost non-/low-responder patients with primary open-angle glaucoma or ocular hypertension: the FUJI study.

PURPOSE: Omidenepag isopropyl (OMDI) is the prodrug of omidenepag, a selective, non-prostaglandin, prostanoid EP2 receptor agonist, which has been shown to lower intraocular pressure (IOP) in patients with glaucoma and ocular hypertension (OHT). This study evaluated the efficacy and safety of OMDI ophthalmic solution 0.002% in patients with primary open-angle glaucoma or OHT who were non-/low responders to latanoprost. STUDY DESIGN: Open-label, multicenter, Phase 3 study (NCT02822742). METHODS: Following 1-4-week washout, patients were treated with latanoprost ophthalmic solution 0.005% during an 8-week run-in period. Patients with ≤15% IOP reduction at the end of the run-in (indicating non-/low response) received OMDI 0.002% (one drop once daily for 4 weeks). The primary endpoint was the change from baseline in mean diurnal IOP at Week 4. RESULTS: In total, 26 patients were treated with OMDI; two withdrew owing to lack of efficacy. The mean diurnal IOP at baseline (end of latanoprost run-in) was 23.1 mmHg (7.6% IOP reduction from end of washout) indicating non-/low response to latanoprost. After 4 weeks of OMDI treatment, mean diurnal IOP was significantly reduced from baseline (-2.99 mmHg; P < 0.0001). No serious adverse events were reported. Adverse events occurred in five patients (19.2%); adverse drug reactions (anterior chamber cell, conjunctival hyperemia, and erythema of eyelid) occurred in two patients (7.7%) and were mild in severity. CONCLUSIONS: In this study, OMDI 0.002% demonstrated a clinically significant reduction in IOP and was well tolerated in patients with primary open-angle glaucoma and OHT who were non-/low responders to latanoprost.

Omidenepag Isopropyl Versus Latanoprost in Primary Open-Angle Glaucoma and Ocular Hypertension: The Phase 3 AYAME Study.

PURPOSE: To evaluate the efficacy and safety of omidenepag isopropyl (OMDI), a selective, non-prostaglandin, prostanoid EP2 receptor agonist, in Japanese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). DESIGN: Phase III, randomized, investigator-masked, active-controlled, parallel-group, noninferiority study (ClinicalTrials.govNCT02623738). METHODS: After a washout period of 1-4 weeks, eligible patients were randomized (1:1) to OMDI 0.002% or latanoprost 0.005% once daily for 4 weeks. Intraocular pressure (IOP) was measured at 9:00 AM, 1:00 PM, and 5:00 PM at weeks 1, 2, and 4. The primary endpoint was the change from baseline in mean diurnal IOP at week 4. The noninferiority margin for OMDI versus latanoprost was 1.5 mm Hg. Adverse events (AEs) were recorded. RESULTS: Of the 190 patients randomized, 189 had at least 1 post-baseline IOP measurement. At baseline, patients who received OMDI or latanoprost had a mean ± SD diurnal IOP of 23.78 ± 1.73 mm Hg and 23.40 ± 1.51 mm Hg, respectively. At week 4, least-squares mean ± SE reduction in IOP from baseline with OMDI (-5.93 ± 0.23 mm Hg) was noninferior to that of latanoprost (-6.56 ± 0.22 mm Hg; 95% confidence interval between groups: 0.01-1.26). The most frequently reported treatment-related ocular AEs (OMDI vs latanoprost) were conjunctival hyperemia (23/94 patients [24.5%] vs 10/96 patients [10.4%]), corneal thickening (11/94 patients [11.7%] vs 1/96 patients [1.0%]), and punctate keratitis (0/94 patients vs 5/96 patients [5.2%]). No serious AEs were observed in either group, and there were no discontinuations related to the study drug. CONCLUSIONS: OMDI 0.002% was noninferior to latanoprost 0.005% in reducing IOP in patients with OHT or POAG and was well tolerated.

Pharmacokinetics, Safety, and Intraocular Pressure-Lowering Profile of Omidenepag Isopropyl, a Selective, Nonprostaglandin, Prostanoid EP2 Receptor Agonist, in Healthy Japanese and Caucasian Volunteers (Phase I Study).

Purpose: Omidenepag isopropyl (OMDI) is a prodrug of OMD, a selective, nonprostaglandin, prostanoid EP2 receptor agonist. This phase I study aimed to investigate the pharmacokinetic properties, safety, and intraocular pressure (IOP)-lowering efficacy of OMDI. Methods: Fourteen healthy male volunteers (7 Japanese and 7 Caucasian) 20-35 years of age received 1 drop of OMDI 0.0025% at 9:00 h in both eyes for 7 days. Blood samples were taken predose and up to 8 h postdose on days 1, 3, and 7. The plasma concentration of OMD was determined using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters measured included the maximum plasma concentration (Cmax) and the half-life (t½) of OMD. IOP, adverse events (AEs), ophthalmic examinations, vital signs, and laboratory values were assessed. Results:Cmax for all subjects was reached after 10-15 min and decreased with a t½ of ∼30 min. Ad hoc statistical analyses found significant differences in some pharmacokinetic parameters between Japanese and Caucasian subjects, likely due to differences in body weight. These differences reduced over 7 days of dosing and were not thought to be clinically meaningful. There was no OMD accumulation after 7 days of repeated dosing. Mean IOP was reduced by ∼4-5 mmHg between baseline and 2 h postdose, remaining stable from day 3 onward. All AEs were mild and considered treatment related. Conclusions: Pharmacokinetic parameters of OMD were similar between Japanese and Caucasian subjects. There was no accumulation of OMD after 7 days of dosing. OMDI was well tolerated and demonstrated clinically significant IOP reductions.

Phase 2, Randomized, Dose-finding Studies of Omidenepag Isopropyl, a Selective EP2 Agonist, in Patients With Primary Open-angle Glaucoma or Ocular Hypertension.

PRéCIS:: Three randomized, multicenter studies demonstrated the stable intraocular pressure-lowering effects and tolerability of omidenepag isopropyl in patients with primary open-angle glaucoma and ocular hypertension; 0.002% was identified as the optimal dose for further investigation. PURPOSE: The purpose of this study was to assess the safety and efficacy of omidenepag isopropyl, a selective EP2 agonist, and to determine the optimal dose for further investigation. PATIENTS AND METHODS: Three randomized, controlled, masked, multicenter studies were conducted in United States (study 1, NCT01868126; study 2, NCT02179008) and Japan (study 3, NCT02623738). Patients were randomized to 1 of 7 omidenepag isopropyl concentrations (0.0003%, 0.001%, 0.0012%, 0.0016%, 0.002%, 0.0025%, and 0.003%), latanoprost (0.005%), or placebo, 1 drop once daily for 28 days (studies 1 and 3) or 90 days (study 2). Primary endpoints were the observed mean diurnal intraocular pressure (IOP) and IOP at each time point on the final visit (studies 1 and 2) and change from baseline in mean diurnal IOP at week 4 (study 3). RESULTS: IOP-lowering effects of omidenepag isopropyl 0.0003% to 0.002% increased dose-dependently. Omidenepag isopropyl 0.002% and 0.0025% resulted in clinically relevant mean diurnal IOP reductions from baseline that were similar to those of latanoprost and superior to placebo (P<0.005). Maximum reductions had already been achieved by week 1, and stable IOP-lowering effects were observed at all postbaseline time points up to 3 months. Most adverse events (AEs) were mild. Conjunctival hyperemia was the most frequently reported AE, the incidence of which increased dose-dependently. The safety profiles of omidenepag isopropyl 0.002% and 0.0025% were similar, with a slightly lower incidence of AEs in the 0.002% group. CONCLUSIONS: Omidenepag isopropyl demonstrated stable IOP-lowering effects and was well tolerated; 0.002% was identified as the optimal dose for phase 3 investigation.