GSK2256294 / GSK - LARVOL DELTA

Technical Feasibility and Protocol Compliance in the Second Stroke Pre-Clinical Assessment Network (ISC 2025) - "The Interventions, also selected through an NIH peer review process, included NanO2 (NuvOx) an oxygen delivery emulsion, tatCN19o (Neurexis) a CaM-kinase II inhibitor, GSK2256098 (GlaxoSmithKline/ETSU) a focal adhesion kinase inhibitor, GSK2256294 (GlaxoSmithKline/OHSU) a soluble epoxide hydrolase inhibitor, and BPN-27332 (Loxagen/MGH) a lipoxygenase inhibitor. The feasibility and protocol compliance seen in SPAN 1 have been replicated in stage 1 of the second trial, SPAN 2.1. Mortality resembles previous experience, with an improved survival in aged mice. SPAN 2 has advanced to Stage 2 where improved dose timing is implemented."

Compliance • Preclinical • Cardiovascular • Obesity

Soluble epoxide hydrolase inhibitors for smoking-associated inflammatory lung diseases and chronic obstructive pulmonary disease: a meta-analytical systematic review of preclinical and clinical studies. (PubMed, Am J Transl Res) - "GSK2256294 inhibited the soluble epoxide hydrolase enzyme in both clinical and preclinical models, exhibiting greater effectiveness in clinical studies and contributing to the anti-inflammatory activity mediated by the eicosatrienoic pathway by reducing the levels of dihydroxyeicosatrienoic acids and leukotoxin-diol. Overall, GSK2256294 was identified as a promising drug for controlling the deleterious manifestations of lung inflammation. Further clinical and preclinical studies are required to ensure consistency among the evidence and identify other biological activities mediated by GSK2256294."

Journal • Preclinical • Review • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: Vanderbilt University Medical Center | N=70 ➔ 16

Enrollment change • Endocrine Disorders • Genetic Disorders • Metabolic Disorders • Obesity

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance (clinicaltrials.gov) - P2 | N=70 | Completed | Sponsor: Vanderbilt University Medical Center | Active, not recruiting ➔ Completed | Trial completion date: Oct 2022 ➔ Nov 2021 | Trial primary completion date: Oct 2022 ➔ Nov 2021

Trial completion • Trial completion date • Trial primary completion date • Endocrine Disorders • Genetic Disorders • Metabolic Disorders • Obesity

Designing a Small Fluorescent Inhibitor to Investigate Soluble Epoxide Hydrolase Engagement in Living Cells. (PubMed, ACS Med Chem Lett) - "Starting from the clinical candidate GSK2256294A, we replaced the triazine moiety with the 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) fluorophore...The developed inhibitor is applicable in a NanoBRET-based assay system suitable for studying sEH target engagement in living cells. Furthermore, the inhibitor can be used to visualize sEH in sEH-transfected HEK293 cells and in primary mouse astrocytes by fluorescence microscopy."

Journal • Alzheimer's Disease • CNS Disorders • Immunology • Inflammation

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance (clinicaltrials.gov) - P2 | N=80 | Active, not recruiting | Sponsor: Vanderbilt University Medical Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Endocrine Disorders • Genetic Disorders • Metabolic Disorders • Obesity

A New Family of Subnanomolar inhibitors of Soluble Epoxide Hydrolase. (PubMed, FASEB J) - "Although several potent sEH inhibitors (sEHI) have been developed, including clinical candidates AR9281, GSK2256294, and EC5026, so far no sEHI has reached the market. Biol. 2020, 1274, 71-99."

Journal • Inflammation • Pain

The soluble epoxide hydrolase inhibitor GSK2256294 decreases the proportion of adipose pro-inflammatory T cells. (PubMed, Prostaglandins Other Lipid Mediat) - "Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation."

Journal • Genetic Disorders • Immunology • Inflammation • Obesity • Oncology • IFNG • TNFA

A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage. (PubMed, Neurocrit Care) - P1/2 | "GSK2256294 administration was safe and well tolerated in critically ill patients with SAH, producing an increase in serum EETs and the EET-to-DHET ratio. Our findings support future studies in a larger population to evaluate the role of sEH inhibition in the prevention of DCI after SAH and other forms of brain injury and inflammatory conditions."

Clinical • Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Immunology • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Vanderbilt University Medical Center; Trial primary completion date: Oct 2021 ➔ Oct 2022

Trial primary completion date • Endocrine Disorders • Genetic Disorders • Metabolic Disorders • Obesity

GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans. (PubMed, Hypertension) - "Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes-a marker of oxidative stress-but does not improve insulin sensitivity or blood pressure."

Clinical • Journal • Genetic Disorders • Hypertension • Immunology • Inflammation • Metabolic Disorders • Obesity • EPHX1

Discovery of soluble epoxide hydrolase inhibitors through DNA-encoded library technology (ELT). (PubMed, Bioorg Med Chem) - "The structure and activity relationship study led to the expansion of the original 1,4-cycloalkyl series to related aniline, piperidine, quinoline, aryl-ether and benzylic series. The 1,3-cycloalkyl chemotype led to the discovery of a clinical candidate (GSK2256294) for COPD."

Journal • Cardiovascular • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • EPHX1

Cytochrome P450-epoxygenated fatty acids inhibit Müller glial inflammation. (PubMed, Sci Rep) - "GSK2256294, a soluble epoxide hydrolase (sEH) inhibitor, significantly reduced PA- and IL-1β-stimulated MC cytokine expression. 11,12-EET and 19,20-EDP were also found to decrease PA- and IL-1β-induced NFκB-dependent transcriptional activity. These data suggest that experimental elevation of 11,12-EET and 19,20-EDP decreases MC inflammation in part by blocking NFκB-dependent transcription and may represent a viable therapeutic strategy for inhibition of early retinal inflammation in DR."

Journal • Diabetic Retinopathy • Immunology • Inflammation • Metabolic Disorders • Ocular Inflammation • Retinal Disorders • CXCL8 • EPHX1 • IL1B • IL6 • TNFA

[VIRTUAL] The Contribution of Arachidonic Acid Metabolites EETs to Inflammation in Obesity (ENDO 2021) - P2 | "EETs are hydrolyzed to less active forms by the enzyme soluble epoxide hydrolase (sEH), and we hypothesized that pharmacologic sEH inhibition with a specific inhibitor GSK2256294 (GSK) in obese patients would decrease AT inflammation... In a pilot study of seven individuals treated with placebo or an sEH inhibitor, we found that the sEH inhibitor decreased pro-inflammatory Th1 cells as compared with placebo in matched AT samples. Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate AT and systemic inflammation and reduce the risk of CVD. Unless otherwise noted, all poster abstracts presented at ENDO 2021 are embargoed until 11 AM Eastern on Saturday, March 20."

Aesthetic Medicine • Cardiovascular • Dyslipidemia • Genetic Disorders • Hypertension • Immunology • Inflammation • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CD8 • EPHX1 • IFNG

[VIRTUAL] The Contribution of Arachidonic Acid Metabolites EETs to Inflammation in Obesity (ENDO 2021) - P2 | "EETs are hydrolyzed to less active forms by the enzyme soluble epoxide hydrolase (sEH), and we hypothesized that pharmacologic sEH inhibition with a specific inhibitor GSK2256294 (GSK) in obese patients would decrease AT inflammation... In a pilot study of seven individuals treated with placebo or an sEH inhibitor, we found that the sEH inhibitor decreased pro-inflammatory Th1 cells as compared with placebo in matched AT samples. Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate AT and systemic inflammation and reduce the risk of CVD. Unless otherwise noted, all poster abstracts presented at ENDO 2021 are embargoed until 11 AM Eastern on Saturday, March 20."

Aesthetic Medicine • Cardiovascular • Dyslipidemia • Genetic Disorders • Hypertension • Immunology • Inflammation • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CD8 • EPHX1 • IFNG

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Vanderbilt University Medical Center; Trial completion date: Oct 2021 ➔ Oct 2022; Trial primary completion date: Oct 2020 ➔ Oct 2021

Trial completion date • Trial primary completion date • Endocrine Disorders • Genetic Disorders • Metabolic Disorders • Obesity

SUSHI: Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial (clinicaltrials.gov) - P1/2; N=20; Completed; Sponsor: Oregon Health and Science University; Active, not recruiting ➔ Completed; Trial completion date: Dec 2021 ➔ Jan 2020

Trial completion • Trial completion date • Hematological Disorders • Ischemic stroke • Subarachnoid Hemorrhage

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Vanderbilt University Medical Center; N=34 ➔ 80; Trial completion date: Oct 2020 ➔ Oct 2021

Enrollment change • Trial completion date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity

To Evaluate Effects of GSK2256294 on Pulmonary Artery Pressure in Healthy Volunteers Under Normoxic and Hypoxic Conditions (clinicaltrials.gov) - P1; N=30; Not yet recruiting; Sponsor: GlaxoSmithKline

New P1 trial • Biosimilar

Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease. (PubMed, PLoS One) - "To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD."

Journal • Preclinical

SUSHI: Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial (clinicaltrials.gov) - P1/2; N=20; Active, not recruiting; Sponsor: Oregon Health and Science University; Recruiting ➔ Active, not recruiting

Enrollment closed