GSK2798745 / GSK - LARVOL DELTA

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2798745 in Participants With Diabetic Macular Edema (clinicaltrials.gov) - P1 | N=16 | Terminated | Sponsor: GlaxoSmithKline | Completed ➔ Terminated; The study was terminated as the study met the prespecified threshold for futility of less than (<) 20 percentage (%), based on interim analysis (IA).

Trial termination • Diabetic Macular Edema • Macular Edema • Ophthalmology

TRPV4 antagonists for the treatment of heart failure: Pathways to two structurally diverse chemotypes (ACS-Fall 2024) - "Further optimization of the pharmacokinetic and physiochemical properties was successful in delivering GSK2798745, which advanced to clinical trials as a first-in-class TRPV4 inhibitor for heart failure...The acyclic amines were hypothesized to exist in a unique intramolecular H-bonded cyclic conformation, which translated into a preferred TRPV4 binding orientation. Modification of the acyclic amine series revealed intriguing strategies to improve potency by electronically modulating separate intramolecular and intermolecular H-bond interactions."

Cardiovascular • Congestive Heart Failure • Heart Failure • Respiratory Diseases

Effect of TRPV4 Antagonist GSK2798745 on Chlorine Gas-Induced Acute Lung Injury in a Swine Model. (PubMed, Int J Mol Sci) - "Exposure to 240 parts per million (ppm) chlorine gas for ≥50 min resulted in acute lung injury characterized by sustained changes in the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PaO2/FiO2), oxygenation index, peak inspiratory pressure, dynamic lung compliance, and respiratory system resistance over 24 h. Chlorine exposure also heightened airway response to methacholine and increased wet-to-dry lung weight ratios at 24 h. Following 55-min chlorine gas exposure, GSK2798745 marginally improved PaO2/FiO2, but did not impact lung function, airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, or histopathology. In summary, in this swine model of chlorine gas-induced acute lung injury, GSK2798745 did not demonstrate a clinically relevant improvement of key disease endpoints."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Anesthesia • Inflammation • Pulmonary Disease • Respiratory Diseases

TRPV4 channels promote vascular permeability in retinal vascular disease. (PubMed, Exp Eye Res) - "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. 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."

Journal • Cardiovascular • Oncology • Retinal Vein Occlusion • TNFA

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2798745 in Participants With Diabetic Macular Edema (clinicaltrials.gov) - P1 | N=17 | Completed | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Completed

Trial completion • Diabetic Macular Edema • Macular Edema • Ophthalmology

Comparing Dynamic Ca2+ Signaling Profiles Activated from Two Different Pathways in Pulmonary Microvascular Endothelial Cells (ATS 2022) - "After an initial baseline recording, cells were either treated with 4α-PDD (TRPV4 activator) and subsequently with GSK2798745 (TRPV4 inhibitor) or with a high K+ solution (TTCC activator) and subsequently with mibefradil (TTCC inhibitor)... Our findings indicate TRPV4 channel and TTCC activation result in spatially and temporally distinct Ca2+ signaling profiles. Future studies will address the specific roles of these profiles and potentially identify new cellular targets for clinical management of ALI."

Acute Lung Injury • Immunology • Inflammation • Respiratory Diseases

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2798745 in Participants With Diabetic Macular Edema (clinicaltrials.gov) - P1 | N=17 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting | N=30 ➔ 17

Enrollment change • Enrollment closed • Diabetic Macular Edema • Macular Edema • Ophthalmology

Study 212669: A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2798745 in Participants With Diabetic Macular Edema (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: Dec 2021 ➔ Jun 2022; Trial primary completion date: Dec 2021 ➔ Jun 2022

Clinical • Trial completion date • Trial primary completion date • Diabetic Macular Edema • Macular Edema • Ophthalmology

Identification, Synthesis, and Characterization of a Major Circulating Human Metabolite of TRPV4 Antagonist GSK2798745. (PubMed, ACS Med Chem Lett) - "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."

Journal • Respiratory Diseases

Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough. (PubMed, ERJ Open Res) - "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."

Clinical • Journal • Pulmonary Disease • Respiratory Diseases

TRPV4 antagonists: a patent review (2015-2020). (PubMed, Expert Opin Ther Pat) - "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."

Journal • Review • Cardiovascular • Congestive Heart Failure • Dermatology • Gastroenterology • Gastrointestinal Disorder • Heart Failure • Oncology • Pain • Respiratory Diseases

Identification of a Human Whole Blood-Based Endothelial Cell Impedance Assay for Assessing Clinical TRPV4 Target Engagement Ex Vivon . (PubMed, J Pharmacol Exp Ther) - "Significance Statement In the absence of a suitable target engagement biomarker, we developed an ex vivo assay to predict the pharmacological activity of the TRPV4 blocker GSK2798745 in healthy volunteers and HF subjects from Phase I/IIa trials. The potency values from the ex vivo assay were consistent with those predicted from a rat in vivo PK/PD model of pulmonary edema, strongly suggest circulating levels of GSK2798745 were sufficient to robustly block TRPV4, supporting use of GSK2798745 for assessing efficacy in HF."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Respiratory Diseases

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2798745 in Subjects With Diabetic Macular Edema (DME) (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: May 2022 ➔ Dec 2021; Trial primary completion date: May 2022 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Diabetic Macular Edema • Macular Edema • Ophthalmology

Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge. (PubMed, Pulm Pharmacol Ther) - P1 | "GSK2798745 did not affect segmental LPS-induced elevation of BAL total protein or neutrophils, despite blood and lung exposures that were predicted to be efficacious. CLINICALTRIALS."

Journal • Acute Respiratory Distress Syndrome • Immunology • Inflammation • Pneumonia • Respiratory Diseases

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2798745 in Subjects With Diabetic Macular Edema (DME) (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: Mar 2021 ➔ May 2022; Trial primary completion date: Mar 2021 ➔ May 2022

Clinical • Trial completion date • Trial primary completion date • Diabetic Macular Edema • Macular Edema • Ophthalmology

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2798745 in Subjects With Diabetic Macular Edema (DME) (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Diabetic Macular Edema • Macular Edema • Ophthalmology • VEGFA

Targeting pulmonary capillary permeability to reduce lung congestion in heart failure: a randomized, controlled pilot trial. (PubMed, Eur J Heart Fail) - "In this pilot trial, GSK2798745 was found to be safe and well-tolerated, with a trend toward improved gas transfer. Further investigation is warranted in larger studies to determine whether treatment with TRPV4 antagonists or alternative treatments targeting capillary permeability might be effective to improve lung congestion, pulmonary gas transfer and clinical status in patients with acute or chronic HF."

Clinical • Journal

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2798745 in Subjects With Diabetic Macular Edema (DME) (clinicaltrials.gov) - P1; N=30; Not yet recruiting; Sponsor: GlaxoSmithKline

Clinical • New P1 trial

Discontinued Drugs for the Treatment of Cardiovascular Disease from 2016 to 2018. (PubMed, Int J Mol Sci) - "Of these, six candidates (MDCO-216, TRV027, ubenimex, sodium nitrite, losmapimod, and bococizumab) were dropped for lack of clinical efficacy, the other six for strategic or unspecified reasons...Four candidate developments (OPC-108459, ONO-4232, GSK-2798745, and TAK-536TCH) were run without biomarkers, which could be used as surrogate endpoints in the 12 cardiovascular drugs discontinued from 2016 to 2018. This review will be useful for those involved in the field of drug discovery and development, and for those interested in the treatment of cardiovascular disease."

Biomarker • Journal • Review

Clinical Pharmacokinetics, Safety, and Tolerability of a Novel, First-in-Class TRPV4 Ion Channel Inhibitor, GSK2798745, in Healthy and Heart Failure Subjects. (PubMed, Am J Cardiovasc Drugs) - P2; "GSK2798745 was well-tolerated in healthy volunteers and patients with stable heart failure. The safety and exposure data obtained in this study allow further evaluation of the drug in long-term clinical studies in heart failure as well as other indications."

Clinical • Journal • PK/PD data

Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4). (PubMed, ACS Med Chem Lett) - "We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times."

Clinical • Journal

Mitochondrial ROS-Induced Ca2+ Influx Via TRPV4 and Mitochondrial Structure/Function in Microvascular Endothelial Cells Isolated from the Sugen/Hypoxia Model of Pulmonary Arterial Hypertension (PAH) (ATS 2019) - "Basal/Maximal respiration as well as extracellular acidification rate (ECAR) was measured using the SeaHorse XFe analyzer, using the MitoStress kit.Results Fission was increased in SuHx-MVEC mitochondria at baseline, but was attenuated following treatment with either 1) MitoQ or 2) TRPV4 inhibitors HC-067047 (HC) or GSK2798745 (GSK2). MitoQ (but not HC or GSK2) treatment improved basal/maximal respiration as well as ECAR in SuHx-MVECs.Conclusion Our results suggest that, in SuHx-MVECs, increased ROS production promotes mitochondrial fragmentation by increasing [Ca2+]i via TRPV4. Inhibiting mtROS-induced Ca2+ influx via TRPV4 improves mitochondrial morphology but not respiration, suggesting that while mtROS-induced fission is Ca2+ dependent, mtROS decreases respiration via additional non Ca2+-dependent mechanisms."