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

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 ; Roberts, Andrew D ; Behm, David J ; 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.

2021-07-01·ERJ open research

Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough

Article

作者: Parker, Sean M ; Morice, Alyn ; Behm, David J ; Marks-Konczalik, Joanna E ; Ludbrook, Valerie J ; Hanrott, Kate E ; Kreindler, James L ; Hewens, Debbie A ; Birring, Surinder S ; McGarvey, Lorcan ; Beerahee, Misba ; Bird, Nick P ; Smith, Jaclyn

Objective:

Airway sensory nerves involved in the cough reflex are activated by adenosine triphosphate (ATP) agonism of P2X purinoceptor 3 (P2X3) receptors. Transient receptor potential vanilloid 4 (TRPV4) channel activation causes ATP release from airway cells, and it is hypothesised that a TRPV4-ATP-P2X3 axis contributes to chronic cough. An adaptive study was run to determine if TRPV4 inhibition, using the selective TRPV4 channel blocker GSK2798745, was effective in reducing cough.

Methods:

A two-period randomised, double blinded, placebo-controlled crossover study was designed with interim analyses for futility and sample size adjustment. Refractory chronic cough patients received either GSK2798745 or placebo once daily for 7 days with a washout between treatments. Pharmacokinetic samples were collected for analysis of GSK2798745 at end of study. The primary end-point was total cough counts assessed objectively during day-time hours (10 h) following 7 days of dosing.

Results:

Interim analysis was performed after 12 participants completed both treatment periods. This showed a 32% increase in cough counts on Day 7 for GSK2798745 compared to placebo; the pre-defined negative criteria for the study were met and the study was stopped. At this point 17 participants had been enrolled (mean 61 years; 88% female), and 15 had completed the study. Final study results for posterior median cough counts showed a 34% (90% credible interval: −3%, +85%) numerical increase for GSK2798745 compared to placebo.

Conclusion:

There was no evidence of an anti-tussive effect of GSK2798745. The study design allowed the decision on lack of efficacy to be made with minimal participant exposure to the investigational drug.

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

合作

2019-02-06

·BioSpace

GSK Cuts Six Respiratory Assets as It Continues to Focus on Oncology Treatments

Courtesy of Willy Barton/Getty Images GlaxoSmithKline has been in the midst of a significant reshaping to focus on pharmaceuticals, particularly a renewed interest in oncology treatments. As a result, the company has made some cuts to its pipeline, including six quietly announced this morning in the company’s year-end report. Willy Barton / Shutterstock.com GlaxoSmithKline has been in the midst of a significant reshaping to focus on pharmaceuticals, particularly a renewed interest in oncology treatments. As a result, the company has made some cuts to its pipeline, including six quietly announced this morning in the company’s year-end report. In a slide-show of graphics used during a conference call with analysts and media members, the company revealed it had terminated eight programs, mostly in its respiratory line. In the small section marked “terminated,” GSK said it shed two treatments for chronic obstructive pulmonary disease, GSK1325756 (danirixin) and GSK2269557 (nemiralisib). It also cut GSK2245035, a TLR7 agonist used for treating asthma and the TRPV4 antagonist GSK2798745, under development for acute respiratory distress syndrome and cough. Additionally, the company cut the combination treatment of GSK2398852 + GSK2315698 (anti-SAP) in transthyretin cardiomyopathy (ATTR-CM) and GSK3008348, an aVb6 antagonist for the treatment of idiopathic pulmonary fibrosis. The respiratory asset cuts are not much of a surprise, as the company has increasingly focused its resources on oncology treatments. In October, Alex Hoos, head of oncology at GSK, indicated that the company was shifting away from its respiratory base due to increased competition and loss of patent exclusivity. In an interview with S&P Global Market Intelligence , Hoos said the company could narrow its drug development focus to aim at products that will generate growth. The Hoos announcement followed the long-term plan for R&D unveiled over the summer by GSK Chief Science Officer and head of R&D, Hal Barron. The company said it will focus on the development of medicines that target mechanisms of action with strong human genetic validations. Those targets have a higher probability of success, which means a shift to a genetics-driven portfolio, the company said. Since taking over the helm of GSK, Chief Executive Officer Emma Walmsley has been driving the company toward its new focus and has reshaped her executive leadership and made several significant deals to support the plan. Among the deals made by GSK, was the December 2018 decision to put down $5.1 billion to acquire Tesaro and its PARP inhibitor, Zejula, which is used as maintenance treatment for ovarian cancer. Barron has touted the belief in PARP inhibitors that “that have been underappreciated in terms of the impact they can have on cancer patients.” More recently, GSK struck a deal with Merck KGaA, Darmstadt, Germany to collaborate on the development and potential commercialization of M7824 , an immunotherapy for difficult to treat cancers. M7824 is an investigational bifunctional fusion protein immunotherapy that has the potential to be a treatment for difficult-to-treat cancers including non-small cell lung and biliary tract cancers. Barron said the alliance with Merck KGaA is an “opportunity to further accelerate our oncology strategy.” In its announcement today, GSK noted that in its oncology pipeline, it has 16 oncology assets in clinical development with a potential for three launches by 2020. In July of 2018, the company only had eight oncology assets in clinical development. The doubling of the number of assets over the past eight months demonstrated the company’s discipline in building its oncology program. Over the course of the next year, the U.K.-based company said it will strengthen its oncology pipeline as it anticipates several key data readouts this year, including one with Zejula as first-line maintenance therapy in ovarian cancer. GSK is also anticipating a respiratory readout this year, its CAPTAIN study of Trelegy, which it expects will support regulatory submission.

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100 项与 GSK-2798745 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
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
糖尿病性黄斑水肿	临床1期	美国	GSK Plc	2020-09-07
糖尿病性黄斑水肿	临床1期	澳大利亚	GSK Plc	2020-09-07
糖尿病性黄斑水肿	临床1期	新西兰	GSK Plc	2020-09-07
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
镇静	临床1期	德国	GSK Plc	2018-06-25

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临床结果

适应症

分期

评价

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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


NCT04292912 (CTgov)	临床1期	糖尿病性黄斑水肿 \| 黄斑水肿	16	GSK2798745	簾築壓築顧膚遞憲鹹構 = 齋鬱顧獵鹹觸淵獵製鏇願襯襯醖鏇衊廠夢廠憲 (鬱膚獵壓壓艱襯齋衊積, 醖構顧糧廠製願壓築窪 ~ 願繭膚廠獵艱積餘積鏇) 更多	-	2024-11-08
NCT03511105 (CTgov)	临床1期	镇静	47	placebo (Placebo)	窪觸繭壓餘鹽艱憲蓋獵(糧齋製窪夢鏇憲遞夢製) = 壓蓋鬱齋遞餘餘鑰夢願蓋憲淵繭範積鑰襯艱築 (鬱觸簾觸簾鏇廠鬱遞範, 蓋網糧鹹壓鬱壓範簾製 ~ 窪醖窪繭膚蓋艱齋築顧) 更多	-	2020-02-05
				LPS+GSK2798745 (GSK2798745)	窪觸繭壓餘鹽艱憲蓋獵(糧齋製窪夢鏇憲遞夢製) = 觸鹹製醖鏇願鬱夢觸鹹蓋憲淵繭範積鑰襯艱築 (鬱觸簾觸簾鏇廠鬱遞範, 網廠築顧鹹鏇選鹽網蓋 ~ 壓繭壓顧膚淵獵艱襯壓) 更多
NCT03372603 (CTgov)	临床1/2期	慢性咳嗽	17	placebo (Placebo)	觸齋壓廠觸淵憲網選願(廠膚鑰淵鹽廠窪憲廠蓋) = 糧衊願網願窪選鹹淵構築夢糧餘膚蓋襯夢網窪 (淵簾網齋顧鹹壓艱衊艱, 鑰構築淵憲獵選衊築衊 ~ 願觸選網窪蓋鑰製觸鏇) 更多	-	2019-10-02
				GSK2798745 (GSK2798745)	觸齋壓廠觸淵憲網選願(廠膚鑰淵鹽廠窪憲廠蓋) = 願網鬱醖選願築夢遞鹽築夢糧餘膚蓋襯夢網窪 (淵簾網齋顧鹹壓艱衊艱, 糧鏇夢窪衊範齋獵製鬱 ~ 衊襯餘鹹衊淵壓構觸淵) 更多
NCT02497937 (CTgov)	临床2期	心脏衰竭	11	placebo (Placebo)	壓憲鑰網膚築淵餘憲憲(齋窪網衊夢觸醖鹹夢襯) = 廠觸鑰鹽鏇膚壓壓顧積襯鏇顧網廠願願積選齋 (醖餘築鹹獵衊鹽築醖夢, 0.98) 更多	-	2018-09-05
				GSK2798745 (GSK2798745 2.4 mg)	壓憲鑰網膚築淵餘憲憲(齋窪網衊夢觸醖鹹夢襯) = 壓壓構鬱膚鑰艱窪膚齋襯鏇顧網廠願願積選齋 (醖餘築鹹獵衊鹽築醖夢, 1.47) 更多