GSK3965193 / GSK - LARVOL DELTA

Mechanical Regulation of Transient Receptor Potential Vanilloid 4 Function in Aging and Cardiovasculature Disease. (PubMed, ACS Appl Mater Interfaces) - "Furthermore, TRPV4 activation regulated stiffness-dependent actin remodeling, endothelial alignment, and cell elongation. Pharmacological inhibition of TRPV4 using GSK2193874 increased endothelial inflammatory responses, supporting a protective role for TRPV4 in endothelial adaptation to pathological mechanical environments.Collectively, these findings highlight TRPV4's contribution to endothelial responses to vascular stiffening and its potential as a therapeutic target for vascular aging and cardiovascular diseases."

Journal • Cardiovascular • Inflammation • TRPV4

Cutaneous TRPV4 Potentiates the Afferent Transmission of Electroacupuncture Stimulation. (PubMed, ACS Omega) - "Conversely, the TRPV4 antagonist GSK2193874 reduced the number of neurons showing basal calcium activity relative to vehicle and significantly attenuated ES-evoked calcium responses compared with the agonist group. These results demonstrate that non-neuronal TRPV4 in the skin potentiates afferent signaling during ES, underscoring a previously overlooked role for neuroimmune interaction in acupuncture signal initiation. These findings improve our understanding of how acupuncture initiates afferent signals at the cellular level and highlight cutaneous TRPV4 as a potential target for modulating ES-evoked afferent signaling."

Journal • TRPV1 • TRPV4

Safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK3965193 in patients with chronic hepatitis B (CHB) (EASL 2026) - P1/2 | "GSK193 at the tested dose was tolerated, showed favorable safety and pharmacokinetic profile, and demonstrated preliminary evidence of antiviral activity through HBsAg reduction, supporting further clinical development of GSK193 as part of a regimen for treating CHB."

Clinical • PK/PD data • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation

TRP-Dependent Calcium Regulation in HCEC-12 Cells: Involvement of Ascorbic Acid and Cannabinoid Receptor Signaling. (PubMed, Int J Mol Sci) - "Adding 1 mM Asc increased [Ca2+]i, which was partially suppressed by the TRPV1 blocker AMG-9810 (AMG) (20 µM) and the TRPV4 blocker GSK2193874 (GSK219) (10 µM)...The inhibitory effect of AM251 suggests a predominant contribution of CB1 receptors. Given the central role of Ca2+ homeostasis in corneal endothelial function and disease, these results may contribute to a better understanding of endothelial pathophysiology and support further investigation of TRPs and cannabinoid signaling as potential targets in corneal disorders."

Journal • Ophthalmology • TRPM8 • TRPV1

Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection (clinicaltrials.gov) - P1/2 | N=74 | Terminated | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Terminated; The study was terminated as a strategic decision

Monotherapy • Trial termination • Hepatitis B • Infectious Disease • Inflammation

TRPV4 mediates macrophage polarization involved in inflammatory root resorption induced by mechanical pressure. (PubMed, Channels (Austin)) - "Treatment with the TRPV4 inhibitor GSK2193874 resulted in a significant downregulation of intracellular Ca2+ concentration and expression levels of iNos and CD86, and a significant upregulation of Arg-1 and CD206 expression levels. Therefore, our study demonstrates that TRPV4 senses mechanical pressure by promoting Ca2+ influx and upregulates the M1/M2 macrophage polarization ratio. In conclusion, our findings indicate that TRPV4 serves as a critical mediator in mechanical pressure-regulated macrophage polarization during OIIRR."

Journal • CD86 • MRC1 • TRPV4

TRPV4 Deficiency Shifts Mitochondrial Dynamics Toward a Fragmented Morphology in Primary Microglia. (PubMed, Cells) - "Furthermore, acute pharmacological TRPV4 inhibition with GSK2193874 did not induce significant mitochondria network fragmentation. Our findings establish TRPV4 as a regulator of mitochondrial dynamics and adaptive responses, highlighting its importance for maintaining homeostasis in microglia and the entire CNS."

Journal

Inhibition of TRPV4 Regulates Mitophagy Through the Sirt1/FoxO1 Signaling Pathway To Alleviate Acute Lung Injury. (PubMed, Inflammation) - "Conversely, TRPV4 inhibition (GSK2193874) or knockout attenuated lung injury, enhanced mitophagic flux, and reduced mitochondrial damage...Genetic or pharmacological inhibition of TRPV4 restored mitophagic clearance of dysfunctional mitochondria, offering a promising therapeutic strategy for septic ALI. These findings highlighted the TRPV4-Sirt1/FoxO1 axis as a novel target for improving outcomes in critical care settings."

Journal • Acute Lung Injury • Critical care • Inflammation • Pneumonia • Respiratory Diseases • PINK1 • PTEN • TRPV4

Transient Receptor Potential Vanilloid 4 Antagonist Eliminated Age-Related Spatial Memory Deficit in Female Sprague Dawley Rats. (PubMed, Neural Plast) - "Furthermore, aged rats exhibited spatial memory decline, which was normalized with TRPV4 antagonist GSK2193874 (GSK219) injection...GSK219 treatment effectively normalized hippocampal SA-β-Gal activity, inflammation, and autophagy in aged rats. TRPV4 hyperactivity was found to induce hippocampal inflammation and neuronal death, leading to spatial memory impairment in normal aging."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • TRPV4

TRPV4 channels mediate exacerbated response to mechanical cues in spontaneously hypertensive rats. (PubMed, J Hypertens) - "While TRPV4 inhibition with GSK2193874 (GSK; 300 nmol/l) or HC067047 (1 μmol/l) did not affect the hypotonic solution induced Pie in Wistar myocytes, it was significantly reduced in SHR...Disruption of caveolae with 5 mmol/l methyl-β-cyclodextrin and inhibition of microtubule polymerization with 10 μmol/l Colchicine, reduced the GSK-sensible component of the hypotonic solution induced Pie...Intact caveolae and microtubule integrity are required for TRPV4 activation in SHR myocytes. In SHR hearts, TRPV4 can be activated by cardiac stretch contributing to the SFR."

Journal • Preclinical • Cardiovascular • Hypertension • TRPV4

Activation of endothelial TRPV4 exacerbates myocardial ischemia-reperfusion injury via vascular integrity impairment. (PubMed, Can J Cardiol) - "Activation of endothelial TRPV4 CECs exacerbates post-IR vascular hyperpermeability and myocardial injury by impairing barrier integrity and promoting apoptosis. Targeting endothelial TRPV4 may represent a promising therapeutic strategy to mitigate myocardial IR injury."

Journal • Cardiovascular • Inflammation • Myocardial Ischemia • Reperfusion Injury • CDH5 • CLDN5 • OCLN • RHOA

Inhibition of transient receptor potential vanilloid 4: A promising novel strategy for myocardial ischemia/reperfusion injury treatment. (PubMed, Biomed Pharmacother) - "Preclinical studies demonstrate that selective TRPV4 antagonists (e.g., HC-067047, GSK2193874) significantly reduce infarct size, preserve cardiac function, suppress arrhythmias, alleviate myocardial stunning, and prevent coronary no-reflow. The age-related upregulation of TRPV4 further highlights its therapeutic relevance in elderly patients. Targeting TRPV4 thus represents a promising strategy to mitigate multifactorial myocardial injury and improve outcomes following reperfusion therapy."

Journal • Review • Cardiovascular • Inflammation • Myocardial Ischemia • Reperfusion Injury • TRPV4

Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection (clinicaltrials.gov) - P1/2 | N=74 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2027 ➔ Apr 2026 | Trial primary completion date: Sep 2027 ➔ May 2025

Enrollment closed • Monotherapy • Trial completion date • Trial primary completion date • Hepatitis B • Infectious Disease • Inflammation

TRPV4 controls circadian and pathological ocular hypertension. (PubMed, J Physiol) - "Microinjection of TRPV4 antagonists HC-067047 and GSK2193874 lowered IOP during the nocturnal OHT phase and in hypertensive eyes treated with dexamethasone or injection of polystyrene microbeads. Conditional ablation of TRPV4 channels from the trabecular meshwork prevented the induction of OHT and protected the eye from glaucoma. These findings bring physiological and pathological mechanisms that mediate OHT into mechanobiological context and identify a novel target for pressure control in glaucoma."

Journal • Cardiovascular • Glaucoma • Ophthalmology

Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection (clinicaltrials.gov) - P1/2 | N=84 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Jan 2027 ➔ Sep 2027 | Trial primary completion date: Jan 2027 ➔ Sep 2027

Trial completion date • Trial primary completion date • Hepatitis B • Infectious Disease • Inflammation

The role of TRPV4 in ferroptosis in MPP+/MPTP-induced Parkinson's disease models. (PubMed, Tissue Cell) - "TRPV4 plays a key role in MPP+/MPTP-induced ferroptosis. Our results indicate that the downregulation of TRPV4 may a represent promising treatment for PD through the inhibition of ferroptosis."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • DMRT1 • GPX4 • TRPV4

Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection (clinicaltrials.gov) - P1/2 | N=84 | Recruiting | Sponsor: GlaxoSmithKline | Phase classification: P2 ➔ P1/2 | N=132 ➔ 84 | Trial completion date: Oct 2027 ➔ Jan 2027 | Trial primary completion date: Oct 2027 ➔ Jan 2027

Enrollment change • Monotherapy • Phase classification • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

TRPV4 inhibition suppresses myocardial ischemic-reperfusion arrhythmia of mice by alleviating calcium handling abnormalities. (PubMed, Heart Rhythm) - "TRPV4 inhibition exerts antiarrhythmic effects post-IR by modulating CaMKII-dependent Ca2+ handling abnormalities, reducing CaT alternans and Ca2+ leak, without affecting APD."

Journal • Preclinical • Cardiovascular • Myocardial Ischemia • Reperfusion Injury • Ventricular Tachycardia

Transient Receptor Potential Vanilloid 4 Calcium-Permeable Channel Contributes to Valve Stiffening in Aortic Stenosis. (PubMed, J Am Heart Assoc) - "These findings reveal a novel mechanism linking TRPV4 to valve stiffening, providing insights into how extracellular matrix mechanical properties drive inflammation and fibrosis in AVS."

Journal • Cardiovascular • Congestive Heart Failure • Dyslipidemia • Fibrosis • Heart Failure • Immunology • Inflammation • Metabolic Disorders • TGFB1 • TRPV4

The Role of TRPV2 Ion Channel in NAMPT Secretion During Cardiac Arrest (AHA 2024) - "NAMPT release from neutrophils is regulated by TRPV2 channel-mediated calcium influx."

Cardiovascular • Inflammation • NAMPT • TRPV2

Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection (clinicaltrials.gov) - P2 | N=132 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Jan 2026 ➔ Oct 2027 | Trial primary completion date: Jan 2026 ➔ Oct 2027

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Nanoparticle Delivery Increases Anti-Nociceptive Efficacy of TRPV4 Receptor Antagonist in Cancer (IASP 2024) - "GSK2193874 is a selective TRPV4 antagonist that can be loaded into nanoparticles (NPs), which can facilitate drug delivery[6-8]... These results demonstrate that TRPV4 plays a role in oral cancer pain and that NP-encapsulated TRPV4 receptor antagonist delivery increases the anti-nociceptive efficacy of TRPV4 receptor antagonist. Future studies are planned to genetically delete TRPV4 on Schwann cells in an oral cancer mouse model to confirm the cell-specific effect of TRPV4 in oral cancer pain."

Clinical • Head and Neck Cancer • Oncology • Oral Cancer • Pain • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Tongue Carcinoma • TRPV4

TRPV4 subserves physiological and pathological elevations in intraocular pressure. (PubMed, Res Sq) - "Microinjection of TRPV4 antagonists HC067047 and GSK2193874 lowered IOP during the nocturnal OHT phase and in hypertensive eyes treated with steroids or injection of polystyrene microbeads...Tonic TRPV4 signaling thus represents a fundamental property of TM biology as a driver of increased in vitro and in vivo outflow resistance. The TRPV4-dependence of OHT under conditions that mimic primary and secondary glaucomas could be explored as a novel target for glaucoma treatments."

Journal • Cardiovascular • Glaucoma • Ophthalmology

THE ROLE OF MECHANICAL STRAIN-INDUCED HOTAIR LNCRNA DOWNREGULATION IN THE PATHOPHYSIOLOGY OF RHEUMATOID ARTHRITIS (EULAR 2024) - "The effects of TRPv4 and Jnk inhibition on HOTAIR levels was uncovered by using specific inhibitors (GSK2193874 (2.5 µM) and KN-93 (50 µM))... Mechanical Strain induced a novel ADAM15-dependent signaling pathway leading to SIRT1 upregulation and energy metabolism alteration in the cell thus contributing to a more resistant and aggressive phenotype of RASF and an increased proinflammatory extracellular milieu in rheumatoid arthritis."

Immunology • Inflammatory Arthritis • Musculoskeletal Diseases • Orthopedics • Rheumatoid Arthritis • Rheumatology • ADAM15 • HOTAIR

TRPV4 modulation participates in paraoxon-induced brain injury via NMDA and NLRP3 regulation. (PubMed, Brain Inj) - "In vivo, we examined the survival rate, behavioral seizures, histopathological alterations, NMDA receptor phosphorylation, as well as the expression of the NLRP3-ASC-caspase-1 complex and downstream inflammatory factors in the POX poisoning model following intervention with the TRPV4 antagonist GSK2193874...Moreover, the TRPV4 antagonist corrected the NMDA-induced increase in inward current and cell death rate, decrease in cell viability, and Ca2+ accumulation. TRPV4 participates in the mechanisms of brain injury induced by POX exposure through NMDA-mediated excitotoxicity and NLRP3-mediated inflammatory response."

Journal • CNS Disorders • Epilepsy • Inflammation • Vascular Neurology • CASP1 • NLRP3