The Role of EP3 Agonism in Intraocular Pressure-Lowering by Sepetaprost, a Novel Dual Agonist of FP and EP3 Receptors, in Monkeys

<b><i>Purpose:</i></b> This study aimed to elucidate the contribution of EP3 receptor agonism to the intraocular pressure (IOP)-lowering effects of sepetaprost, a novel dual agonist of FP and EP3 receptors, in monkeys.<b><i>Methods:</i></b> The agonistic activities of ONO-AG-367 (the active metabolite of sepetaprost) and latanoprost acid toward FP and EP3 receptors were assessed using a cell-based assay. The IOP-lowering effects of sepetaprost and latanoprost were compared in ocular normotensive monkeys. The involvement of EP3 receptor activation in sepetaprost-induced IOP reduction was evaluated by intracameral administration of an EP3 antagonist followed by topical sepetaprost. Aqueous humor dynamics (AHD) were assessed via fluorophotometry in ocular hypertensive monkeys. Outflow facility was measured by tonography in ocular normotensive monkeys. Additionally, the IOP-lowering efficacy of sepetaprost was examined in latanoprost low-responder monkeys.<b><i>Results:</i></b> ONO-AG-367 exhibited potent agonistic activity at both FP and EP3 receptors, whereas latanoprost acid selectively activated the FP receptor. Sepetaprost elicited greater and longer-lasting IOP reduction than latanoprost. Pretreatment with an EP3 antagonist significantly attenuated the IOP-lowering effect of sepetaprost at 26 h. In the AHD study, sepetaprost enhanced outflow facility and uveoscleral outflow. Tonographic assessment confirmed a significant increase in outflow facility following sepetaprost treatment. Sepetaprost also effectively reduced IOP in latanoprost low-responder monkeys.<b><i>Conclusions:</i></b> EP3 receptor agonism contributes to the longer-lasting IOP-lowering effect of sepetaprost in monkeys. These findings suggest that sepetaprost enhances uveoscleral outflow and improves facility in the trabecular outflow pathway, and may provide effective IOP lowering when there is a suboptimal response to latanoprost.