GSK3965193 / GSK - LARVOL DELTA

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

Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model. (PubMed, J Thorac Cardiovasc Surg) - "Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant."

Journal • Preclinical • Cardiovascular • Inflammation • Pulmonary Disease • Reperfusion Injury • Respiratory Diseases • Transplantation • CLDN5 • HMGB1 • OCLN • TJP1

Electroacupuncture ameliorates neuroinflammation by inhibiting TRPV4 channel in ischemic stroke. (PubMed, CNS Neurosci Ther) - "EA may inhibit neuroinflammation and exhibit a protective effect against ischemic brain injury by suppressing TRPV4 and the subsequent M1 polarization of microglia/macrophages."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Vascular Neurology • CCL2 • IL1B • IL6 • TNFA • TRPV4

Endothelial Cell Calcium Influx Mediates Trauma-induced Endothelial Permeability. (PubMed, Ann Surg) - "This study illuminates a novel mechanism of post-injury endotheliopathy involving Ca2+ influx via the TRPV4 channel. TRPV4 inhibition mitigates trauma-induced endothelial permeability. Moreover, widespread endothelial Ca2+ influx may contribute to trauma-induced hypocalcemia. This study provides the mechanistic basis for the development of Ca2+-targeted therapies and interventions in the care of severely injured patients."

Journal • Endocrine Disorders

Functional TRPV4 Status Sets the Rate of Cytogenesis in Autosomal Recessive Polycystic Kidney Disease (ARPKD) During Variations in Dietary Potassium (KIDNEY WEEK 2023) - "Overall, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells thus attenuating (high activity) or accelerating (low activity) ARPKD progression. Augmenting TRPV4 activity by increased dietary K+ intake may have therapeutic potential in PKD."

Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • TRPV4

Surfactant found in cleaning products, 4-tert-octylphenol, causes airway sensory nerves firing and airway smooth muscle contraction (ERS 2023) - "We then pharmacologically investigated ion channels known to play a role in airway reflexes and determined that antagonists for TRPM3 (isosakuranetin, 5µM) and TRPV4 (GSK2193874, 10µM) inhibited 4-t-OP (10µM)-induced nerve depolarisation by 56% and 44% respectively...This suggests that 4-t-OP acts via two distinct pathways involving TRPM3 and TRPV4. Our data shows that 4-t-OP interacts with airway sensory nerves and airway smooth muscle via activation of TRPM3 and TRPV4, suggesting a novel mechanism by which alkylphenols may contribute to respiratory symptoms following cleaning product exposure.; Pulmonary function testing; Physiology; Imaging; Endoscopy and interventional pulmonology; Surgery; Cell and molecular biology; General respiratory patient care; Epidemiology"

Surfactant • TRPM3

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

Combination therapy • Monotherapy • Phase classification • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Mechanical overload induces TMJ disc degeneration via TRPV4 activation. (PubMed, Oral Dis) - "Our findings suggest TRPV4 plays a pivotal role in the pathogenesis of mechanical overload-induced TMJ disc degeneration and may be a promising target for the treatment of degenerative changes of the TMJ disc."

Journal • Inflammation

Low temperature reduces occludin expression in bronchial epithelial cells: Implications in cold-induced asthma. (PubMed, Mol Immunol) - "We identified a potential mechanism underlying cold-induced asthma exacerbation involving Nedd4-2-mediated occludin proteolysis and airway epithelial barrier disruption."

Journal • Asthma • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • OCLN

TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium. (PubMed, Physiol Rep) - "These beneficial effects were negated by a concomitant administration of an orally active TRPV4 antagonist, GSK2193874, resulting in greater kidney weight, accelerated cystogenesis, and augmented renal injury. High KB/C diet also exacerbated renal manifestations of ARPKD, consistent with deficient TRPV4 activity in cystic cells. Overall, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells thus attenuating (high activity) or accelerating (low activity) ARPKD progression."

Journal • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

The Ca channel TRPV4 is dispensable for Ca influx and cell volume regulation during hypotonic stress response in human keratinocyte cell lines. (PubMed, Cell Calcium) - "We interfered with TRPV4 function in two human keratinocyte cell lines (HaCaT and NHEK-E6/E7) by using two TRPV4-specific inhibitors (RN1734 and GSK2193874), and by creating a CRISPR/Cas9-mediated genetic TRPV4 knockout in HaCaT cells...Accordingly, hypotonicity-induced cell swelling, downstream activation of VRAC currents as well as subsequent RVD were unaffected both in TRPV4 inhibitor-treated keratinocytes and in HaCaT-TRPV4 cells. In summary, our study shows that keratinocytes do not require TRPV4 for coping with hypotonic stress, which implies the involvement of other, yet unidentified Ca channels."

Journal • Preclinical

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

TRPV4 channel is involved in HSV-2 infection in human vaginal epithelial cells through triggering Ca oscillation. (PubMed, Acta Pharmacol Sin) - "Pretreatment with specific TRPV4 channel inhibitors, GSK2193874 (1-4 μM) and HC067047 (100 nM), or gene silence of the TRPV4 channel not only suppressed HSV-2 infectivity but also reduced HSV-2-induced cytokine and chemokine generation in VK2/E6E7 cells by blocking Ca influx through TRPV4 channel. These results reveal that the TRPV4 channel works as a Ca-permeable channel to facilitate HSV-2 infection in host epithelial cells and suggest that the design and development of novel TRPV4 channel inhibitors may help to treat HSV-2 infections."

Journal • Herpes Simplex • Infectious Disease

Role of Cholesterol in the Regulation of Hydrogen Sulfide Signaling within the Vascular Endothelium. (PubMed, Antioxidants (Basel)) - "The NaHS-induced vasodilation following MBCD treatment in large arteries was blocked by TRPV4 and BK channel inhibitors (GSK219384A, 300 nM and iberiotoxin, 100 nM, respectively)...Proximity ligation assay studies did not show a correlation between EC PM cholesterol content and the association of TRPV4 and BK. Collectively, these results demonstrate that EC PM cholesterol limits HS-induced vasodilation through effects on EC TRPV4 and BK channels."

Journal

Combination treatment of a PAPD5/7 inhibitor with an antisense oligonucleotide bepirovirsen with concurrent dosing shows additive HBsAg decreases in the AAV-HBV mouse model (EASL-ILC 2022) - P2b | "This current work describes investigation of combinations of a PAPD5/7 inhibitor, GSK3965193, (GSK193) with bepirovirsen (BPV, antisense oligonucleotide against HBV, currently completed a Ph2b study (study NCT04449029)) in a mouse model of HBV infection. Combinations of a PAPD5/7 inhibitor (GSK193) and antisense oligonucleotide (bepirovirsen) provide additional reductions in HBsAg when dosed concurrently in the AAV-HBV mouse model of HBV. Concurrent dosing of these compounds is also superior in terms of maximal HBsAg suppression to sequential dosing preclinically."

Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Study of GSK3965193 in Healthy Participants and Alone and in Combination With Bepirovirsen in Participants Living With Chronic Hepatitis B Infection (clinicaltrials.gov) - P1/2 | N=132 | Recruiting | Sponsor: GlaxoSmithKline | Not yet recruiting ➔ Recruiting | Phase classification: P2 ➔ P1/2

Combination therapy • Enrollment open • Monotherapy • Phase classification • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Study of GSK3965193 in Healthy Participants and Alone and in Combination With Bepirovirsen in Participants Living With Chronic Hepatitis B Infection (clinicaltrials.gov) - P2 | N=132 | Not yet recruiting | Sponsor: GlaxoSmithKline

Combination therapy • Monotherapy • New P2 trial • Hepatitis B • Hepatology • Infectious Disease • Inflammation