zenuzolac (VGX-1027) / GeneOne - LARVOL DELTA

GIT 27 Modulates TLR4/Src/NOX2 Signaling Pathway: A Potential Therapeutic Strategy to decrease Neuroinflammation, Oxidative Stress and Neuronal Cell Death in Parkinson's Disease. (PubMed, Free Radic Biol Med) - "Mechanistically, GIT 27 markedly suppressed glial activation and neuroinflammation through the inhibition of the TLR4/Src/NOX2 signaling pathway, leading to a downregulation of oxidative stress and neuronal damage as well as modulating ferroptosis. These findings highlight the TLR4/Src/NOX2 axis as a key driver of neurodegeneration and support, for the first time, the potential of GIT 27 as a therapeutic strategy for modulating neuroinflammation and preserving neuronal integrity in PD through this signaling pathway."

IO biomarker • Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • TLR4

Multi-modal microcarriers reprogram mitochondrial metabolism and activate efferocytosis in macrophages for osteoporotic bone repair. (PubMed, Biomaterials) - "In this work, we developed a VGX-1027-loaded mesoporous silica nanosphere composite PLLA microcarrier...In a postmenopausal osteoporosis animal model, PMVGX exhibited remarkable efficacy in repairing osteoporotic bone defects. This proof-of-concept study demonstrates that our multi-modal microcarrier effectively regulates macrophage functions via mitochondrial homeostasis, efferocytosis, and exosome content, offering great potential for osteoporotic bone repair."

Journal • Inflammation • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2 | N=132 | Completed | Sponsor: GeneOne Life Science, Inc. | Active, not recruiting ➔ Completed

Trial completion • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

NEUROPROTECTIVE EFFECTS OF GIT27 VIA TLR4 PATHWAY MODULATION IN AN IN VIVO MODEL OF PARKINSON'S DISEASE (ADPD 2025) - "In conclusion, this study consolidates the pathological role of TLR4 in driving neuroinflammation and highlights GIT -27 as a promising therapeutic candidate for treating neurodegenerative disorders like PD."

IO biomarker • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • FAP • GFAP

SPP1+ macrophages promote head and neck squamous cell carcinoma progression by secreting TNF-α and IL-1β. (PubMed, J Exp Clin Cancer Res) - "SPP1 + Macs increase the secretion of TNF-α and IL-1β via the NF-kappa B pathway to promote HNSCC cell proliferation, and TNF-α and IL-1β in turn upregulate the expression of OPN in tumor cells and macrophages; thus, SPP1 + Macs may be a candidate target through which antitumor efficacy can be enhanced."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IL1B • SPP1 • TNFA

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2 | N=132 | Active, not recruiting | Sponsor: GeneOne Life Science, Inc. | Trial completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2 | N=132 | Active, not recruiting | Sponsor: GeneOne Life Science, Inc. | Trial completion date: Jun 2023 ➔ Dec 2023

Trial completion date • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2 | N=132 | Active, not recruiting | Sponsor: GeneOne Life Science, Inc. | Trial completion date: Mar 2023 ➔ Jun 2023

Trial completion date • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2 | N=132 | Active, not recruiting | Sponsor: GeneOne Life Science, Inc. | Trial completion date: Oct 2022 ➔ Mar 2023

Trial completion date • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2 | N=132 | Active, not recruiting | Sponsor: GeneOne Life Science, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2; N=132; Recruiting; Sponsor: GeneOne Life Science, Inc.; Trial completion date: Nov 2021 ➔ Sep 2022; Trial primary completion date: Oct 2021 ➔ May 2022

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2; N=132; Recruiting; Sponsor: GeneOne Life Science, Inc.; Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (COVID-19) (clinicaltrials.gov) - P2; N=132; Not yet recruiting; Sponsor: GeneOne Life Science, Inc.; Initiation date: Nov 2020 ➔ Feb 2021

Clinical • Trial initiation date • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

2nd phase clinical trial of S. Korean drug firm's COVID-19 treatment candidate approved in U.S [Google translation] (Yonhap News Agency) - "South Korean drug firm GeneOne Life Science Inc. said Monday it has won approval to conduct a second phase clinical trial of its treatment candidate for the novel coronavirus in the United States. The U.S. Food and Drug Administration (FDA) have approved a phase two study of GLS-1027, an oral drug candidate known to prevent severe pneumonia caused by COVID-19 infection. The candidate will be administered to 132 adult COVID-19 patients from the moment of their infection to evaluate the efficacy of preventing pneumonia, the company said."

New P2 trial • Infectious Disease • Novel Coronavirus Disease

GLS-1027 for the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection (clinicaltrials.gov) - P2; N=132; Not yet recruiting; Sponsor: GeneOne Life Science, Inc.

Clinical • New P2 trial • Infectious Disease • Novel Coronavirus Disease • Pneumonia

Free light chains injure proximal tubule cells through STAT1-HMGB1-TLR axis. (PubMed, JCI Insight) - "Countering TLRs 2, 4, and 6 through GIT-27 or specific TLR-siRNAs reduced downstream cytokine responses...PTCs exposed to FLCs released HMGB1, which induced TLRs 2, 4, 6 expression and downstream inflammation. Blocking FLCs' endocytosis, Stat1 knock-down, HMGB1 inhibition, and TLR knock-down each rescued PTCs from FLC-induced injury."

IO Biomarker • Journal • Immunology • Nephrology

Safety, bioavailability, and pharmacokinetics of VGX-1027-A novel oral anti-inflammatory drug in healthy human subjects. - Clin Pharmacol Drug Dev - "No accumulation of the drug was observed after day 1, indicating that steady-state concentrations were attained with single and multiple dosing for 5 days. Approximately 90% of the administered dose was excreted in urine as unchanged drug."

Journal • Biosimilar • Immunology • Rheumatoid Arthritis

Effects of GIT-27NO, a NO-donating compound, on hepatic ischemia/reperfusion injury. (PubMed, Int J Immunopathol Pharmacol) - "GIT-27NO is a NO-derivative of the toll-like receptor 4 antagonist VGX-1027 that has been shown to possess both antineoplastic and immunomodulatory properties in vitro and in vivo...These effects were almost similar to that of the positive control drug dimethyl fumarate. These data suggest that the beneficial effect of GIT-27NO in the hepatic IRI can be secondary to anti-oxidative effects and hepatocyte necrosis reduction probably mediated by NO release."

Journal

The potent immunomodulatory compound VGX-1027 regulates inflammatory mediators in CD4 T cells, which are concomitant with the prevention of neuroimmune dysregulation in BTBR T Itpr3/J mice. (PubMed, Life Sci) - "Moreover, this agent was also found to significantly decrease IL-1β, IL-6, TNF-α, IFN-γ, COX-2, and NOS2 levels and increase IL-10 expression at the protein and mRNA level in brain tissues. Based on results using BTBR mice, our data provide the first evidence that VGX-1027 could potentially be used for the amelioration of autism-like symptoms."

Journal

Interleukin-1 beta induces autophagy of mouse preimplantation embryos and improves blastocyst quality. (PubMed, J Cell Biochem) - "...Furthermore, autophagy activation mainly occurs in 2 to 4 cell embryo and blastocyst, 20 ng/mL IL-1β into culture medium can effectively enhance levels of messenger RNA and protein of autophagy-related-factors in 2 to 4 cell embryos and blastocyst, while these factors reduce in VGX-1027 (IL-1β inhibitor) groups that also reduce the quality of blastocyst. Effects of IL-1β on the development of embryo reduced in 20 ng/mL IL-1β supplemented group when 5 mM 3-methyladenine (3-MA) was also added, which used to inhibit autophagy activation in endogenous PtdIns3Ks signal pathway. Our current results show that exogenous IL-1β can effectively induce autophagy in mouse embryos at stages of 2 to 8 cell and blastocyst, that also help to improve the quality of blastocyst."

Journal • Preclinical

Protective effects of VGX-1027 in PM-induced airway inflammation and bronchial hyperresponsiveness. (PubMed, Eur J Pharmacol) - "Mechanistically, VGX-1027 inhibited PM-induced activation of the TLR4-NF-κB-p38 MAPK and NLRP3-caspase-1 pathways as well as the dysregulation of mitochondrial fusion/fission proteins in vivo and in vitro. VGX-1027 may be a potential prophylactic treatment for PM-induced acute lung injury that has airway inflammation, BHR and mitochondrial damage."

Journal