Human experience and efficacy of omidenepag isopropyl (Eybelis®; Omlonti®): Discovery to approval of the novel non-prostaglandin EP2-receptor-selective agonist ocular hypotensive drug

IF 4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Current Opinion in Pharmacology Pub Date : 2024-01-01 DOI:10.1016/j.coph.2023.102426
Najam A. Sharif
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Abstract

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 (Ki = 3.6 nM) and which potently generates intracellular cAMP in living cells (EC50 = 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.

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omidenepag isopropyl(Eybelis®;Omlonti®)的人体体验和疗效:新型非前列腺素 EP2 受体选择性激动剂降眼压药物从发现到获批的过程
全世界有超过 7500 万人患有与眼压过高(OHT)相关的视网膜和视神经退行性疾病,这些疾病会造成视力损伤,甚至导致失明。近年来,为了寻找新型药物疗法来防治眼压过高症并降低副作用,一些新出现的候选药物已进入人体概念验证阶段。其中一种化合物是非前列腺素(non-prostaglandin,non-PG)EP2受体选择性激动剂(omidenepag isopropyl ester)。Omidenepag(OMD;游离酸形式)是一种新型非前列腺素,能以高亲和力(Ki = 3.6 nM)选择性地结合并激活人类前列腺素受体(EP2R),并能在活细胞中有效地产生细胞内 cAMP(EC50 = 3.9-8.3 nM)。OMD 能明显下调人小梁网(TM)细胞中的 COL12A1 和 COL13A1 mRNA,而小梁网是一种与 OHT 发病机制有关的组织。在眼压正常的兔子、狗和猴子身上,以及在眼压过高(OHT)的赛诺摩格斯猴(Cynomolgus Monkeys)身上,奥米地尼帕异丙酯(OMDI)以 0.0001-0.01% 的剂量单次局部眼部(t.o.)灌注后,能有效降低眼压(IOP)。在狗和猴中重复眼局部注射 OMDI 后,未观察到降低眼压的反应。在兔子和猴子身上发现,布林佐胺、噻吗洛尔和溴莫尼定对 OMDI 的降眼压作用具有相加作用。OMDI 0.002% t.o.通过刺激 OHT 猴的常规(TM)和葡萄膜巩膜(UVSC)流出房水(AQH)来降低眼压。在一项第三阶段临床研究中,0.002% OMDI(每天一次,每次口服)可将 OHT/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,并可维持 12 个月。在另一项为期一个月的临床研究中,0.002% OMDI 的降眼压效果与前列腺素 FP 受体激动剂拉坦前列素(0.005%)的降眼压效果相当,因此 OMDI 的效果不优于拉坦前列素。OHT/OAG 患者在使用 OMDI(0.002%,每天两次,每次点滴)和噻吗洛尔(0.05%,每天两次,每次点滴)时,眼压降低的效果也是相加的。对拉坦前列素(0.005%,口服,每日一次)反应较低或无反应的 OHT/POAG 患者在改用 OMDI 0.002%(口服,每日一次)后,眼压显著降低(额外降低约 3 mmHg)。在 OHT/POAG 患者使用 0.002 % OMDI 一年、每天一次口服后,未发现全身或眼部不良反应(如虹膜颜色变化/上眼睑沟加深/睫毛生长异常)。不过,OMDI 会引起短暂的结膜充血。OMDI 的这些特性使其成为治疗 OHT 和各种类型青光眼的合适新药,尤其是在涉及眼压升高的情况下。
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来源期刊
CiteScore
8.80
自引率
2.50%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Current Opinion in Pharmacology (COPHAR) publishes authoritative, comprehensive, and systematic reviews. COPHAR helps specialists keep up to date with a clear and readable synthesis on current advances in pharmacology and drug discovery. Expert authors annotate the most interesting papers from the expanding volume of information published today, saving valuable time and giving the reader insight on areas of importance.
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