Ocular Hypotensive Effect of ONO-9054, an EP3/FP Receptor Agonist: Results of a Randomized, Placebo-controlled, Dose Escalation Study.
To assess pharmacodynamic and safety profiles of ONO-9054 following single and multiple day dosing in subjects with ocular hypertension or open-angle glaucoma.



This was a phase I, single-center, randomized, double-masked, placebo-controlled dose-escalation study. Nine subjects were randomized to each of ONO-9054 3, 10, 20, 30 μg/mL and 12 to placebo. Subjects received a single drop to each eye at 07:00±30 minutes (single dose). Following a 4-day no-treatment period, subjects were dosed once daily for 14 consecutive days (multiple day dosing). Intraocular pressure (IOP) was measured regularly and compared with baseline measurements. Ocular examinations assessed safety and tolerability.



Mean IOP decreased dose dependently. Following single dosing, IOP decreased from 22.9±4.0 to 15.9±2.3 mm Hg (ONO-9054, 30 μg/mL) at peak effect 9 hours postdose; the reduction in placebo-treated subjects was from 22.3±2.4 to 21.5±3.3 mm Hg. Following multiple day dosing, the greatest reduction in IOP occurred 1 hour postdose on day 18, from 23.3±0.6 to 15.1±2.4 mm Hg (ONO-9054, 10 μg/mL); the smallest reduction at this time was from 23.9±0.8 to 18.6±2.0 mm Hg (ONO-9054, 3 μg/mL). Pressures remained reduced on day 19, 25 hours after the last dose, when the lowest measurement was 15.8±2.1 mm Hg (ONO-9054, 10 μg/mL). Anterior uveitis and vitreous detachment were each reported in 2 subjects and considered moderate by the Investigator. Ocular hyperemia and tolerability symptoms were generally mild and transient.



ONO-9054 was well-tolerated and elicited dose-dependent reductions in IOP, which were sustained for at least 24 hours following 2 weeks of consecutive daily dosing.
*Indiana University School of Medicine, Indianapolis, IN †Ono Pharma UK Ltd, London, UK ‡Omar Consulting Group LLC, Princeton Junction §Ono Pharma USA, Lawrenceville, NJ ∥Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY.
Alon
A
Harris
Caroline L
CL
Ward
Cheryl L
CL
Rowe-Rendleman
Takafumi
T
Ouchi
Andrew
A
Wood
Akifumi
A
Fujii
Janet B
JB
Serle
D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005902:Glaucoma, Open-Angle / Q000188:drug therapy*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009798:Ocular Hypertension / Q000188:drug therapy*; D010082:Oxepins / Q000494:pharmacology / Q000627:therapeutic use*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D014065:Tonometry, Ocular
D000959:Antihypertensive Agents; D010082:Oxepins; D011982:Receptors, Prostaglandin; 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