IOP‐lowering effect and ocular toxicity of ONO‐0476, a prodrug of a novel prostanoid EP2 receptor agonist, in normotensive cynomolgus monkeys

AbstractPurpose ONO‐0476 is a prodrug of ONO‐AE9‐078, a potent and selective prostanoid EP2 receptor agonist manufactured by ONO Pharmaceutical Co., Ltd. The purpose of this study is to evaluate the IOP‐lowering effect and ocular toxicity of ONO‐0476 in cynomolgus monkeys.Methods The binding affinity and agonistic activity of ONO‐0476 and ONO‐AE9‐078 for the prostanoid receptors were evaluated. Male cynomolgus monkeys received single or repeated topical dosing of ONO‐0476 or current prostaglandin analogues (latanoprost, travoprost, tafluprost, bimatoprost) at a volume of 30 uL. The IOP was evaluated by using applanation pneumatonometer. Ocular toxicity was evaluated by using portable slit lamp, laser flare photometry, and ultrasound pachymetry in a 4‐week repeated dosing study in monkeys.Results ONO‐AE9‐078 had high selectivity and high affinity for the prostanoid EP2 receptor (EC50 value was 2.3 nmol/L). Single dosing of ONO‐0476 (0.3 ug/mL or more) reduced IOP in a dose‐dependent manner. IOP‐lowering effects were sustained through 24 h following a single dosing. Repeated dosing (once daily for one week) of ONO‐0476 (0.3 ug/mL) reduced IOP more potently than the current prostaglandin analogues. During 4‐week repeated dosing of ONO‐0476 (1 ug/mL), there were no evidence of significant toxicity.Conclusion ONO‐0476 causes potent and sustained IOP reduction, and has good tolerability following topical dosing. ONO‐0476 is an attractive candidate for treatment of glaucoma and ocular hypertension. Commercial interest