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 mu g/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 mu g/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 mu g/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.)