Ocular hypotensive effect of the novel EP3/FP agonist ONO-9054 versus Xalatan: results of a 28-day, double-masked, randomised study.

BACKGROUND/AIMS: ONO-9054 is being developed for the reduction of intraocular pressure (IOP) in patients with ocular hypertension (OHT) and open-angle glaucoma (OAG). This study compared the novel dual EP3/FP agonist ONO-9054 with the FP agonist Xalatan. METHODS: Adults (n=123) with bilateral mild/moderate OAG or OHT, with unmedicated IOP of ≥24 mm Hg at 8:00 hours, ≥21 mm Hg at 10:00 hours and ≤36 mm Hg, were randomised 1:1 to receive ONO-9054 (0.003%, 30 µg/mL) or Xalatan (0.005%, 50 µg/mL) once daily for 28 days. RESULTS: Day 29 mean diurnal IOP was -7.2 mm Hg for ONO-9054 vs -6.6 mm Hg for Xalatan. At 08:00 hours, the IOPs were comparable, and at all later time points the decrease in IOP was greater for ONO-9054. On day 29, the odds of a mean IOP reduction of ≤-25%, ≤-30% and ≤-35% for ONO-9054 were 2.39, 2.37 and 4.85 times more, respectively, than the odds for Xalatan (p<0.05, post hoc analyses). The percentage of subjects achieving target IOPs on day 29 (≤17, ≤16 and ≤15 mm Hg) was greater for ONO-9054 than for Xalatan; the odds of achieving an IOP ≤15 mm Hg for ONO-9054 were 2.4 times more than the odds for Xalatan (p<0.01, post hoc analysis). CONCLUSIONS: Subjects randomised to receive ONO-9054 were more likely to achieve a greater per cent reduction in IOP and were more likely to achieve target IOPs than those receiving Xalatan. The effects of ONO-9054 in reducing IOP appear to persist longer than those of Xalatan. TRIAL REGISTRATION NUMBER: NCT02083289, Results.

A Novel Dual Agonist of EP3 and FP Receptors for OAG and OHT: Safety, Pharmacokinetics, and Pharmacodynamics of ONO-9054 in Healthy Volunteers.

PURPOSE: The use of a dual prostaglandin E3 (EP3) and prostaglandin F (FP) receptor agonist is a novel approach for the reduction of intraocular pressure (IOP) in open angle glaucoma and ocular hypertension and, as such, ONO-9054 may have benefits over existing therapies. The objectives of this phase I study were to assess the safety, tolerability, systemic pharmacokinetics (PK), and pharmacodynamics (PD) profiles of ONO-9054 (Sepetoprost), the prodrug of ONO-AG-367, in healthy, normotensive adults. METHODS: In this randomized, double-masked, placebo-controlled, single-dose escalating study, 48 male and female healthy volunteers each received a single drop of ONO-9054 0.3, 1.0, 3.0, 10.0, 20.0, or 30.0 µg/mL, or matching placebo in each eye. Blood samples of PK were taken up to 24 hours post dose; ocular and systemic safety, tolerability, and PD assessments were conducted up to approximately 72 hours post dose, and on day 7 at the follow-up visit. RESULTS: We found ONO-9054 was safe and well tolerated and ONO-AG-367 exhibited dose-dependent systemic PK with rapid elimination. The effect of PD was assessed by reduction in IOP, with the maximum change from baseline in IOP in these normotensive individuals of -28.23% achieved at the 30.0 µg/mL dose at 9 hours post administration. CONCLUSIONS: A single dose of the novel EP3 and FP receptor agonist ONO-9054 was safe and well tolerated in healthy volunteers at doses between 0.3 and 30.0 µg/mL and resulted in a significant reduction in intraocular IOP with maximum reduction at 9 hours post dose. This supports further evaluation of ONO-9054 for the treatment of ocular hypertension and open angle glaucoma. (ClinicalTrials.gov number, NCT01508988.).