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

Invest Ophthalmol Vis Sci. 2015 Dec;56(13):7963-70. doi: 10.1167/iovs.15-18166.


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.).

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antihypertensive Agents / administration & dosage
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / pharmacokinetics*
  • Double-Blind Method
  • Female
  • Glaucoma, Open-Angle / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Ocular Hypertension / drug therapy*
  • Oxepins / administration & dosage*
  • Oxepins / adverse effects
  • Oxepins / pharmacology*
  • Receptors, Prostaglandin / agonists*
  • Receptors, Prostaglandin E, EP3 Subtype / agonists*
  • Young Adult


  • Antihypertensive Agents
  • ONO-AG-367
  • Oxepins
  • Receptors, Prostaglandin
  • Receptors, Prostaglandin E, EP3 Subtype
  • prostaglandin F2alpha receptor
  • propan-2-yl 4-(6-(4-(2,5-difluorophenoxy)-3-hydroxybut-1-en-1-yl)-7-hydroxyoctahydro-2H-cyclopenta(b)oxepin-3-yl)butanoate

Associated data

  • ClinicalTrials.gov/NCT01508988