A Three Part, First-in-human, Randomized, Double-masked, Placebo-Controlled, Safety, Tolerability and Early Efficacy Study of MGV354 in Healthy Subjects and in Patients With Ocular Hypertension or Glaucoma

The purpose of this study is to determine if the clinical profile of topical-ocular MGV354 merits further development for the indication of lowering intraocular pressure (IOP).

开始日期2016-03-02

申办/合作机构

Alcon Research Ltd.

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100 项与 MGV-354 相关的临床结果

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100 项与 MGV-354 相关的转化医学

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100 项与 MGV-354 相关的专利（医药）

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项与 MGV-354 相关的文献（医药）

2021-01-02·Xenobiotica4区 · 医学

Understanding metabolism related differences in ocular efficacy of MGV354

4区 · 医学

Article

作者: Prasanna, Ganesh ; Kim, Sean ; Mogi, Muneto ; Ehara, Takeru ; Dumouchel, Jennifer L. ; Argikar, Upendra A. ; Breen, Chris ; Adams, Christopher M.

MGV354 was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. MGV354 is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. MGV354 has been shown to robustly lower IOP over 24 h after a single topical ocular drop in rabbit and monkey pharmacology models. However, MGV354 failed to produce similar results in patients with ocular hypertension or open-angle glaucoma. With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism was significantly different from animal metabolism. The present study documents the investigation of metabolism of MGV354 in an effort to understand potential differences in biotransformation pathways of MGV354 in rabbits, monkeys, and humans. Overall twenty-six metabolites, formed via oxidative and conjugative pathways, were identified in vitro and in vivo. In vitro hepatic metabolism was qualitatively similar across species, with minor but distinct differences. There were no observable interspecies differences in the hepatic and ocular metabolism of MGV354. Although ocular metabolism was not as extensive as hepatic, the results do not explain the lack of efficacy of MGV354 in clinical studies.

2018-08-01·American Journal of Ophthalmology2区 · 医学

A Randomized, Controlled Phase I/II Study to Evaluate the Safety and Efficacy of MGV354 for Ocular Hypertension or Glaucoma

2区 · 医学

Article

作者: Sall, Kenneth ; Mogi, Muneto ; He, Yunsheng ; Wirta, David ; Peace, James ; Wald, Michael ; Prasanna, Ganesh ; Watts, Jen ; Grosskreutz, Cynthia ; Adams, Christopher ; Huttner, Kenneth ; Yan, Jing-He ; Seaman, John ; Walters, Tom ; Newton, Ronald ; Ni, Xiao ; Stacy, Rebecca ; Kolega, Randall

PURPOSETo assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma.DESIGNDouble-masked, randomized, and vehicle-controlled study.METHODSParts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once-daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multisite trial that evaluated intraocular pressure (IOP)-lowering efficacy of the MTD administered nightly for 1 week in 50 patients with minimum IOP of 24 mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at day 8 compared to baseline (ClinicalTrials.govNCT02743780).RESULTSThere was no difference in favor of MGV354 for IOP lowering; change from baseline to day 8 in mean diurnal IOP was -0.6 mm Hg for MGV354-treated patients and -1.1 mm Hg for vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia.CONCLUSIONSOverall, MGV354 0.1% demonstrated no statistically significant effect compared to vehicle in lowering IOP based on the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology.

2018-04-02·Investigative Opthalmology & Visual Science2区 · 医学

A Novel Selective Soluble Guanylate Cyclase Activator, MGV354, Lowers Intraocular Pressure in Preclinical Models, Following Topical Ocular Dosing

2区 · 医学

ArticleOA

作者: Ehara, Takeru ; Prasanna, Ganesh ; Adams, Christopher ; Mogi, Muneto ; Li, Byron ; Newton, Ronald ; Xiang, Chuanxi ; Ng, Christopher Thow Hing ; Kim, Sean ; McAllister, Cale ; Yang, Louis ; Topley, Todd ; Ferrara, Luciana ; Stacy, Rebecca ; Towler, Christopher ; Ghosh, Malay ; Rice, Dennis S.

PurposeThe nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate.MethodsChanges to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354.ResultssGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted.ConclusionsMGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies.

100 项与 MGV-354 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
开角型青光眼	临床2期	-	Alcon Research Ltd.	2016-03-02

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02743780 (Pubmed \| Am J Ophthalmol) 人工标引	临床1/2期	高眼压症 \| 青光眼	50	MGV354	(製蓋壓獵範簾獵網襯積) = 獵齋壓鹽廠願餘夢鬱鏇鑰膚選鹽選鏇糧願鹽夢 (糧餘繭範築網遞獵蓋遞 )	不佳	2018-08-01
				Placebo	(製蓋壓獵範簾獵網襯積) = 壓鹹選構構願夢鑰淵窪鑰膚選鹽選鏇糧願鹽夢 (糧餘繭範築網遞獵蓋遞 )