Phase I, Open-Label, Multi-Center Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of GSK2798745 After 28 Day Repeat Oral Administration to Adults With Diabetic Macular Edema

The study will be composed of 3 periods for all participants: Screening, 28-day Treatment period, and Follow-up visit (approximately 28 days after the final dose).

开始日期2020-09-07

申办/合作机构

GSK Plc

NCT03511105 / Terminated临床1期

A Randomised, Placebo-controlled, Double-blind (Sponsor Open), Segmental LPS Challenge Study to Investigate the Pharmacodynamics of GSK2798745 in Healthy Participants

The primary objective of the study is to investigate the effect of GSK2798745 on alveolar-septal barrier permeability following LPS challenge in healthy subjects. The influx of protein-rich fluid into the lung due to damage to the alveolar capillary barrier, with resultant adverse effects on respiratory function, is a fundamental underlying defect in Acute Respiratory Distress Syndrome (ARDS). In this Phase 1, proof-of-mechanism study, a LPS challenge will be used as a surrogate injury model to investigate the effects of Transient receptor potential vanilloid 4 (TRPV4) channel blockade on alveolar-septal barrier permeability in man. This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), segmental LPS challenge study of GSK2798745 in healthy subjects. Subjects will be randomised in a ratio of 1:1 to take 2 single doses of either 4.8 milligrams GSK2798745 followed by 2.4 milligrams GSK2798745 after 12 hours or a dose of placebo followed by another dose of placebo after 12 hours. The first dose will be administered on Day 1 at 2 hours before Baseline bronchoalveolar lavage (BAL) sampling from a segment in the left lower lobe of lung. LPS 4 nanogram per kilogram will subsequently be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of study treatment will be administered 10 hours after LPS challenge followed by post-dose BAL sampling on Day 2. Each subject will take approximately 5 weeks to complete the study.

开始日期2018-06-25

申办/合作机构

GSK Plc

[+1]

NCT03372603 / Terminated临床1/2期

A Placebo-controlled, Double-blind (Sponsor Open), Randomized, Crossover Study to Assess the Efficacy, Safety, and Tolerability of GSK2798745 in Participants With Chronic Cough

GSK2798745 is a potent and selective transient receptor potential vanilloid 4 (TRPV4) channel blocker being investigated for the treatment of chronic cough. This is a multi-center, randomized, placebo-controlled, double-blind, two-period crossover study with a purpose to evaluate efficacy and safety of GSK2798745. Each subject will have 2 treatment periods, and will be randomized to one of the following treatments in each period: A) Placebo matching to GSK2798745 once daily for 7 days. B) 4.8 milligrams (mg) GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 6 days. There will be a washout period of 14 to 21 days between the treatment periods. A maximum of 48 subjects will be enrolled in the study and the total duration of participation in the study will be maximum of 10 and a half weeks including follow-up visit.

开始日期2018-04-05

申办/合作机构

GSK Plc

[+1]

100 项与 GSK-2798745 相关的临床结果

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100 项与 GSK-2798745 相关的转化医学

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100 项与 GSK-2798745 相关的专利（医药）

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项与 GSK-2798745 相关的文献（医药）

2023-03-01·Experimental eye research

TRPV4 channels promote vascular permeability in retinal vascular disease

Article

作者: Shishido, Yuji ; Sugiura, Akemi ; Toui, Amane ; Shimazawa, Masamitsu ; Moriguchi, Yukiko ; Tanaka, Miruto ; Sugaru, Eiji ; Nakamura, Shinsuke ; Watanabe, Shuzo ; Hara, Hideaki ; Nishinaka, Anri ; Ohara, Kentaro ; Shimada, Kaoru

This study aimed to determine the role of transient receptor potential vanilloid 4 (TRPV4), a calcium (Ca²⁺)-permeable cation channel, in the pathophysiology of retinal vascular disease. The retinal vein occlusion (RVO) murine model was created by irradiating retinal veins using lasers. TRPV4 expression and localization were evaluated in RVO mice retinas. In addition, we examined the effects of TRPV4 antagonists (RQ-00317310, HC-067047, GSK2193874, and GSK2798745) on retinal edema, blood flow, and ischemic areas in RVO mice. Furthermore, changes in the retinal expression of tumor necrosis factor (TNF)-α and aquaporin4 (AQP4) by RQ-00317310 were analyzed using Western blot. We also assessed the barrier integrity of epithelial cell monolayers using trans-endothelial electrical resistance (TEER) in Human Retinal Microvascular Endothelial Cells (HRMECs). The expression of TRPV4 was significantly increased and co-localized with glutamine synthetase (GS), a Müller glial marker, in the ganglion cell layer (GCL) of the RVO mice. Moreover, RQ-00317310 administration ameliorated the development of retinal edema and ischemia in RVO mice. In addition, the up regulation of TNF-α and down-regulation of AQP4 were lessened by the treatment with RQ-00317310. Treatment with GSK1016790A, a TRPV4 agonist, increased vascular permeability, while RQ-00317310 treatment decreased vascular endothelial growth factor (VEGF)- or TRPV4-induced retinal vascular hyperpermeability in HRMECs. These findings suggest that TRPV4 plays a role in the development of retinal edema and ischemia. Thus, TRPV4 could be a new therapeutic target against the pathological symptoms of retinal vascular diseases.

2021-09-09·ACS medicinal chemistry letters3区 · 医学

Identification, Synthesis, and Characterization of a Major Circulating Human Metabolite of TRPV4 Antagonist GSK2798745

3区 · 医学

Article

作者: Briand, Jacques ; Rivero, Ralph A ; Graczyk-Millbrandt, Grazyna ; Behm, David J ; Roberts, Andrew D ; McAtee, John J ; Erhard, Karl ; Lawhorn, Brian G ; Pero, Joseph E ; Holt, Dennis A

GSK2798745, an antagonist of the transient receptor potential vanilloid 4 (TRPV4) ion channel, was recently investigated in clinical trials for the treatment of cardiac and respiratory diseases. Human plasma and urine samples collected from healthy volunteers following oral administration were analyzed to identify circulating and excreted metabolites of the parent drug. One major circulating metabolite (1) was found in pooled human plasma samples, accounting for approximately half of the observed drug-related material. Isolation of metabolite 1 from urine samples followed by MS and NMR studies led to a putative structural assignment of 1 where hydroxylation of GSK2798745 occurred on the central ring, producing a penta-substituted cyclohexane structure containing three stereocenters. Two unique chemical syntheses of the proposed structure were developed to confirm the identity of metabolite 1 and provide access to gram quantities for biological characterization.

2021-09-02·Expert opinion on therapeutic patents2区 · 医学

TRPV4 antagonists: a patent review (2015–2020)

2区 · 医学

Review

作者: Brnardic, Edward J. ; Lawhorn, Brian G. ; Behm, David J.

Introduction: Transient receptor potential vanilloid 4 (TRPV4) is an ion channel that is widely expressed and is activated by numerous chemical, osmotic and mechanical stimuli. By modulating Ca²⁺ entry, TRPV4 regulates cellular signaling associated with a variety of (patho)physiological processes and is a target of interest for treatment of human diseases including heart failure, respiratory diseases, gastrointestinal disorders, dermatological conditions, pain and cancer, among others.Areas covered: This article reviews small molecule TRPV4 antagonists and new therapeutic use claims disclosed in the patent literature from 2015 to 2020, including applications covering the first potent and selective TRPV4 clinical candidate and other advanced chemotypes.Expert opinion: TRPV4 has proven to be a tractable target and significant progress in discovery of TRPV4 antagonists has been realized in recent years. Several unique chemical templates with drug-like properties inhibit the channel and show efficacy in models that suggest their potential for treatment of a variety of diseases. While compelling clinical efficacy has not yet been seen in the limited early studies conducted with GSK2798745, evaluation of TRPV4 antagonists in larger trials across several indications is warranted given the availability of high-quality candidates and the promise of therapeutic benefit based on pre-clinical evidence.

项与 GSK-2798745 相关的新闻（医药）

2021-05-12

·GlobeNewswire

Diabetic Macular Edema Pipeline Sees Expansion Owing to Key

Los Angeles, USA, May 12, 2021 (GLOBE NEWSWIRE) -- Diabetic Macular Edema Pipeline Sees Expansion Owing to Key Players, Key Therapies and Research & Programmes Diabetic Macular Edema Pipeline Insight report offers deep insights into emerging Diabetic Macular Edema pipeline therapies with an analysis of 50+key players and 50+key therapies. DelveInsight’s ‘Diabetic Macular Edema (DME) Pipeline Insights’ report provides a holistic view of the DME pipeline therapies that are under development in pre-clinical as well as clinical stages of development and growth prospects across the Diabetic Macular Edema landscape. Key takeaways of the Diabetic Macular Edema Pipeline report: Got queries? Want to know more? Request for Sample @ Diabetic Macular Edema Emerging Therapies and Forecast Diabetic Macular Edema: Overview Macular edema is a condition characterized by the build-up of fluid in the macula, an area in the center of the retina. The excess build-up results in the swelling and thickening of the macula leading to distorted vision. It is referred to as Diabetic Macular Edema (DME) as it is caused by a complication of diabetes called diabetic retinopathy. For more information on emerging drugs, visit Diabetic Macular Edema Pipeline Analysis The DME pipeline report proffers a rich coverage of the therapeutics by development stage, product type, and route of administration, molecule type, and MOA type for Diabetic Macular Edema across the complete product development cycle, including all clinical and non-clinical stages. Diabetic Macular Edema Pipeline Drugs Request for Sample to know which drug is expected to outperform @ Diabetic Macular Edema Pipeline Analysis, Key Companies, and Futuristic Trends Diabetic Macular Edema Therapeutics Assessment The Diabetic Macular Edema Pipeline report proffers exhaustive insights into active pipeline assets segmented by Stage, Product Type, Route of Administration, Molecule Type, Target, and Indications of various drugs. By Product Type By Stage By Molecule Type By Route of Administration By Mechanism of Action By Targets By Stage and Route of AdministrationBy Stage and Product Type Get in touch with our Business executive for Rich and Deep Market Assessment and Consulting Solutions The Diabetic Macular Edema pipeline report puts on the table business opportunities, threats, prospective collaborations, strong competitors, growth strategies, and failed as well as discontinued drugs that will help the clients to keep a track of the ongoing trials, recent happenings in the DME domain. Scope of the Report Coverage: GlobalKey Players: Kodiak Sciences, Novartis Pharmaceuticals, Adverum Biotechnologies, KalVista Pharmaceuticals, Momenta Pharmaceuticals, Roche, Regeneron Pharmaceuticals, Exonate, Opthea Limited, SciFluor Life Sciences, AsclepiX Therapeutics, RemeGen, UNITY Biotechnology, Celltrion, Bio-Thera Solutions, Ripple Therapeutics, GrayBug Vision, Oxurion, Aerie Pharmaceuticals, GlaxoSmithKline, Boehringer Ingelheim, and Apexian Pharmaceuticals among others.Key Diabetic Macular Edema Pipeline Therapies: KSI 301, LKA651, ADVM-022, KVD001, MYL-1701P, Faricimab, REGN 910-3, EXN407, OPT-302, SF0166, AXT107, Brolucizumab, RC28-E, UBX1325, CT-P42, BAT5906, IBE-814, GB-102, THR-149, AR-13503, GSK2798745, BI 1026706, and APX3330 among others. Reach out how novel therapies are transforming the DME landscape @ Diabetic Macular Edema Pipeline Table of Contents Visit to know more of what’s covered @ Diabetic Macular Edema Emerging Therapies Related Reports Chronic Pain Associated With Painful Diabetic Neuropathy MarketDelveInsight's "Chronic Pain Associated with Painful Diabetic Neuropathy - Market Insights, Epidemiology, and Market Forecast-2030" report. Diabetic Foot Ulcers MarketDelveInsight’s ‘Diabetic Foot Ulcer (DFU) - Market Insights, Epidemiology, and Market Forecast—2030’ report. Diabetic Foot MarketDelveInsight's "Diabetic Foot - Market Insights, Epidemiology, and Market Forecast-2030" report. Diabetic Eye Disease MarketDelveInsight's "Diabetic Eye Disease - Market Insights, Epidemiology, and Market Forecast-2030" report. Diabetic Ketoacidosis MarketDelveInsight's "Diabetic Ketoacidosis (DKA) - Market Insights, Epidemiology, and Market Forecast-2030" report. Diabetic Gastroparesis Market SizeDelveInsight’s ‘Diabetic Gastroparesis (DGp) - Market Insights, Epidemiology and Market Forecast-2030’ report offers a detailed analysis of therapies and key pharmaceutical companies including Allergan Evoke Pharma Inc., Theravance Biopharma, Censa Pharmaceuticals, CinDome Pharma, Takeda (Millennium Pharmaceuticals, Inc.), Bird Rock Bio, and others. Diabetic Kidney Disease MarketDelveInsight's "Diabetic Kidney Disease (DKD) - Market Insights, Epidemiology, and Market Forecast-2030" report. Related Posts Understanding The Increasing Prevalence Of Diabetes And Its ComplicationsDiabetic Peripheral Neuropathy Market Landscape Diabetic Peripheral Neuropathy Medications About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports Pharma companies by providing end-to-end comprehensive solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve. For more insights, visit Pharma, Healthcare, and Biotech News

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100 项与 GSK-2798745 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
慢性咳嗽	临床2期	英国	GSK Plc	2018-04-05
心脏衰竭	临床2期	英国	GSK Plc	2014-06-09
肺水肿	临床2期	英国	GSK Plc	2014-06-09
黄斑水肿	临床1期	美国	GSK Plc	2020-09-07
黄斑水肿	临床1期	澳大利亚	GSK Plc	2020-09-07
黄斑水肿	临床1期	新西兰	GSK Plc	2020-09-07
糖尿病性黄斑水肿	临床1期	英国	GSK Plc	2020-08-20

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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


NCT03511105 (CTgov)	临床1期	-	47	placebo (Placebo)	築鹹廠構糧齋鑰鬱醖獵(餘襯願鹽觸壓積範廠窪) = 遞願膚膚窪鹽範壓顧鏇鏇淵顧繭醖顧膚鏇淵廠 (壓鑰蓋繭憲蓋鬱鏇襯淵, 繭蓋製顧壓網窪廠鹹襯 ~ 願選鹽遞鏇鹽襯鹹觸蓋) 更多	-	2020-02-05
				LPS+GSK2798745 (GSK2798745)	築鹹廠構糧齋鑰鬱醖獵(餘襯願鹽觸壓積範廠窪) = 窪遞艱憲廠觸構醖觸鹽鏇淵顧繭醖顧膚鏇淵廠 (壓鑰蓋繭憲蓋鬱鏇襯淵, 觸積積窪醖夢鹽醖鏇鹽 ~ 構餘鹹蓋鹽鹹觸製製製) 更多
NCT03372603 (CTgov)	临床1/2期	慢性咳嗽	17	placebo (Placebo)	醖鑰糧鹽觸艱簾觸鹹膚(顧淵積遞簾繭襯構簾構) = 膚繭齋淵築壓網餘窪鬱繭鏇淵鹹網餘獵廠顧廠 (淵夢製醖齋顧選積觸網, 憲願鬱醖範鬱簾衊簾願 ~ 鹽糧繭遞鏇網夢範襯願) 更多	-	2019-10-02
				GSK2798745 (GSK2798745)	醖鑰糧鹽觸艱簾觸鹹膚(顧淵積遞簾繭襯構簾構) = 構鹹築遞鹽製築範襯獵繭鏇淵鹹網餘獵廠顧廠 (淵夢製醖齋顧選積觸網, 製衊鏇範觸壓簾鹽夢顧 ~ 製鹹膚淵壓膚憲糧築衊) 更多