Sharif Najam A
Eye-ACP Duke-National University of Singapore Medical School, Singapore; Singapore Eye Research Institute (SERI), Singapore; Institute of Ophthalmology, University College London (UCL), London UK; Imperial College of Science and Technology, St. Mary's Campus, London UK; Department of Pharmacy Sciences, Creighton University, Omaha, NE USA; Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, Texas USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX USA.
Curr Opin Pharmacol. 2024 Feb;74:102426. doi: 10.1016/j.coph.2023.102426. Epub 2024 Jan 1.
More than 75 million people worldwide suffer from ocular hypertension (OHT)-associated retinal and optic nerve degenerative diseases that cause visual impairment and can lead to blindness. In an effort to find novel pharmaceutical therapeutics to combat OHT with reduced side-effect potential, several emerging drug candidates have advanced to human proof-of-concept in recent years. One such compound is a nonprostaglandin (non-PG) EP2-receptor-selective agonist (omidenepag isopropyl ester). Omidenepag (OMD; free acid form) is a novel non-PG that selectively binds to and activates the human EP2-prostglandin receptor (EP2R) with a high affinity (K = 3.6 nM) and which potently generates intracellular cAMP in living cells (EC = 3.9-8.3 nM). OMD significantly downregulated COL12A1 and COL13A1 mRNAs in human trabecular meshwork (TM) cells, a tissue involved in the pathogenesis of OHT. Omidenepag isopropyl (OMDI) potently and efficaciously lowered intraocular pressure (IOP) in ocular normotensive rabbits, dogs, and monkeys, and also in ocular hypertension (OHT) Cynomolgus monkeys, after a single topical ocular (t.o.) instillation at doses of 0.0001-0.01%. No reduction in IOP-lowering response to OMDI was observed after repeated t.o. dosing with OMDI in dogs and monkeys. Additive IOP reduction to OMDI was noted with brinzolamide, timolol, and brimonidine in rabbits and monkeys. OMDI 0.002% t.o. decreased IOP by stimulating the conventional (TM) and uveoscleral (UVSC) outflow of aqueous humor (AQH) in OHT monkeys. In a Phase-III clinical investigation, 0.002% OMDI (once daily t.o.) reduced IOP by 5-6 mmHg in OHT/primary open-angle glaucoma (POAG) patients (22-34 mmHg baseline IOPs) that was maintained over 12-months. In an additional month-long clinical study, 0.002% OMDI induced IOP-lowering equivalent to that of latanoprost (0.005%), a prostanoid FP-receptor agonist, thus OMDI was noninferior to latanoprost. Additive IOPreduction was also noted in OHT/OAG patients when OMDI (0.002%, once daily t.o.) and timolol (0.05%, twice daily t.o.) were administered. Patients with OHT/POAG who were low responders or nonresponders to latanoprost (0.005%, q.d.; t.o.) experienced significant IOP-lowering (additional approximately 3 mmHg) when they were switched over to OMDI 0.002% (q.d.; t.o.). No systemic or ocular adverse reactions (e.g. iris color changes/deepening of the upper eyelid sulcus/abnormal eyelash growth) were noted after a year-long, once-daily t.o. dosing with 0.002 % OMDI in OHT/POAG patients. However, OMDI caused transient conjunctival hyperemia. These characteristics of OMDI render it a suitable new medication for treating OHT and various types of glaucoma, especially where elevated IOP is implicated.
全球超过7500万人患有与高眼压（OHT）相关的视网膜和视神经退行性疾病，这些疾病会导致视力损害并可能导致失明。为了寻找具有降低副作用潜力的新型药物疗法来对抗高眼压，近年来有几种新兴的候选药物已进入人体概念验证阶段。其中一种化合物是一种非前列腺素（non-PG）EP2受体选择性激动剂（奥米地帕异丙酯）。奥米地帕（OMD；游离酸形式）是一种新型非PG，它以高亲和力（K = 3.6 nM）选择性地结合并激活人EP2前列腺素受体（EP2R），并在活细胞中有效产生细胞内cAMP（EC = 3.9 - 8.3 nM）。OMD显著下调人小梁网（TM）细胞中的COL12A1和COL13A1 mRNA，小梁网是一种参与高眼压发病机制的组织。奥米地帕异丙酯（OMDI）在正常眼压的兔、狗和猴以及高眼压（OHT）食蟹猴中，以0.0001 - 0.01%的剂量单次局部滴眼（t.o.）后，能有效且显著地降低眼压（IOP）。在狗和猴中重复局部滴眼给予OMDI后，未观察到对OMDI降低眼压反应的减弱。在兔和猴中，发现布林佐胺、噻吗洛尔和溴莫尼定与OMDI联合使用可进一步降低眼压。0.002%的OMDI局部滴眼通过刺激高眼压猴的房水（AQH）经传统（TM）和葡萄膜巩膜（UVSC）途径流出而降低眼压。在一项III期临床研究中，0.002%的OMDI（每日一次局部滴眼）使高眼压/原发性开角型青光眼（POAG）患者（基线眼压为22 - 34 mmHg）的眼压降低5 - 6 mmHg，且这种降低持续了12个月。在另一项为期一个月的临床研究中，0.002%的OMDI降低眼压的效果等同于前列腺素FP受体激动剂拉坦前列素（0.005%），因此OMDI不劣于拉坦前列素。当给予OMDI（0.002%，每日一次局部滴眼）和噻吗洛尔（0.05%，每日两次局部滴眼）时，高眼压/开角型青光眼患者的眼压也有额外降低。对拉坦前列素（0.005%，每日一次；局部滴眼）反应不佳或无反应的高眼压/POAG患者，改用0.002%的OMDI（每日一次；局部滴眼）后，眼压显著降低（额外降低约3 mmHg）。在高眼压/POAG患者中，每日一次局部滴眼给予0.002%的OMDI长达一年后，未观察到全身或眼部不良反应（如虹膜颜色改变/上睑沟加深/睫毛异常生长）。然而，OMDI会引起短暂的结膜充血。OMDI的这些特性使其成为治疗高眼压和各种类型青光眼的合适新药，特别是在眼压升高的情况下。
