title: A Novel Dual Agonist of EP3 and FP Receptors for OAG and OHT: Safety, Pharmacokinetics, and Pharmacodynamics of ONO-9054 in Healthy Volunteers.
abstract: OBJECTIVE
  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.).
authors.affiliation: Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Suto
authors.affiliation: Ono Pharma USA, Inc., Lawrenceville, New Jersey, United States.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Rowe-Rendleman
authors.affiliation: Ono Pharmaceutical Co., Ltd., Chuo-ku, Osaka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ouchi
authors.affiliation: Ono Pharma UK Ltd., London, United Kingdom.
authors.forename: Alam
authors.initials: A
authors.lastname: Jamil
authors.affiliation: Ono Pharma USA, Inc., Lawrenceville, New Jersey, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.affiliation: Ono Pharma UK Ltd., London, United Kingdom.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Ward
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D005902:Glaucoma, Open-Angle / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009798:Ocular Hypertension / Q000188:drug therapy*; D010082:Oxepins / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000819:agonists*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists*; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; C000607346:ONO-AG-367; D010082:Oxepins; D011982:Receptors, Prostaglandin; D058308:Receptors, Prostaglandin E, EP3 Subtype; C034671:prostaglandin F2alpha receptor; C000607345:propan-2-yl 4-(6-(4-(2,5-difluorophenoxy)-3-hydroxybut-1-en-1-yl)-7-hydroxyoctahydro-2H-cyclopenta(b)oxepin-3-yl)butanoate