A Novel Non‐Prostaglandin EP2‐Receptor Agonist for Glaucoma Treatment: Omidenepag Isopropyl (DE‐117) (2020)

Purpose Elevated intraocular pressure (IOP) is often associated with Primary Open‐Angle Glaucoma (POAG), an optic neuropathy that afflicts millions of people and which can cause blindness if left untreated. Omidenepag Isopropyl (OMDI; DE‐117) is a novel pro‐drug non‐prostaglandin (PG) which hydrolyzes to release its active free acid form (Omidenepag; OMD) into the aqueous humor (AQH) after topical ocular (t.o.) instillation. The purpose of the current studies was to characterize OMDI and OMD in several in vitro and in vivo model systems in order to determine its IOP‐lowering and other pharmacological properties. Methods Well‐accepted in vitro cell‐based assays and in vivo IOP measurement techniques were utilized in the current studies. Results OMD was found to be a highly selective EP2 receptor (EP2R) agonist that bound to the EP2R with a high affinity (K i = 3.6 nM) and which potently increased intracellular cAMP (EC 50 = 8.3 nM). Once daily (q.d.), single t.o. dosing with OMDI (0.0001–0.01%) potently and efficaciously lowered IOP in ocular normotensive rabbits, dogs and monkeys, and also in ocular hypertensive (OHT) monkeys. Repeated t.o. dosing with OMDI in dogs did not cause tachyphylaxis of IOP reduction.Additive IOP‐lowering to OMDI was observed with Timolol, Brimonidine and Brinzolamide in rabbits and monkeys . OMDI 0.002% t.o. lowered IOP by increasing AQH efflux via trabecular meshwork (TM) and uveoscleral (UVSC) outflow pathways in OHT monkey eyes. In a phase‐3 clinical study , 0.002% OMDI (q.d.; t.o.), an optimal dose, lowered IOP by 5–7 mmHg in OHT/POAG patients (baseline IOPs of 22–34 mmHg) that was maintained over 12‐months with equivalent efficacy to Xalatan (0.005%, q.d.; t.o.). OHT/POAG patients that were low‐ or non‐responders to Xalatan (0.005%, q.d.; t.o.) exhibited significant IOP‐lowering (additional 3 mmHg) when switched to OMDI 0.002% (q.d.; t.o.). OMDI was well tolerated and produced transient conjunctival hyperemia, and mild iritis and macular edema (ME) in a few patients. However, no iris color changes, DUES, or abnormal eyelash growth were noted after 12‐month q.d. t.o. dosing with 0.002% OMDI, unlike FP‐receptor PG agonists (Bimatoprost and Latanoprost). Additive IOP‐lowering was also observed in OHT/POAG patients when OMDI (0.002%; q.d.) and Timolol (a known ocular hypotensive beta‐antagonist; 0.05%, b.i.d.) were t.o. instilled. Conclusion In conclusion, the non‐prostaglandin organic molecule, OMD, is a highly selective and potent EP2R agonist whose isopropyl ester (OMDI) was shown to be a potent and efficacious ocular hypotensive agent in several animal species and in the OHT/POAG patient population studied. OMDI promoted AQH outflow via both the TM and UVSC pathways to lower IOP, and it achieved a comparable ocular hypotensive efficacy to Latanoprost (Xalatan 0.005% q.d.; t.o.). Additional IOP reduction was observed in Xalatan‐non/low responders when switched over to 0.002% OMDI. Additive IOP‐lowering efficacy was also observed when OMDI was t.o. dosed along with other ocular hypotensive drugs. These pharmacological and clinical efficacy features of OMDI support further development of this drug candidate for treating OHT and glaucoma.