OXC-201 / Karolinska Institute, Stockholm University, University of Texas, Oxcia - LARVOL DELTA

Oxcia welcomes the European Medicines agency’s (EMA) decision to grant Orphan Drug Designation (ODD) for OXC-201 for idiopathic pulmonary fibrosis (IPF). (Cision) - "Clinical trials are due to start in 2027."

New trial • Orphan drug • Idiopathic Pulmonary Fibrosis

Ogg1 regulates TGF‑β-Smad3 signalling and fibrosis progression in chronic kidney disease. (PubMed, Commun Biol) - "Mechanistically, Ogg1 interacts with phosphorylated Smad3 in the nucleus and promotes transcriptional regulation of profibrotic genes. Pharmacological inhibition of Ogg1 with TH5487 alleviates fibrosis in both UUO and AA nephropathy models, supporting Ogg1 as a potential therapeutic target in CKD."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • OGG1 • SMAD3 • TGFB1

TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950. (PubMed, Commun Biol) - "Notably, inhibitors of the DNA repair glycosylase hOGG1 remain effective in L353P mutant PBMCs from FCAS patients and L351P in mice, at doses where the canonical NLRP3 inhibitor MCC950 is ineffective. Our findings uncover an additional druggable mechanism for inflammasome regulation via interference with oxidized DNA sensing, offering innovative therapeutic opportunities for autoinflammatory disease."

Journal • Inflammation • IL1B • NLRP3

RM1mAb avoids Intracellular degradation to Synergistically inhibit NLRP3 Inflammasome Activation in Familial Cold Autoinflammatory Syndrome. (PubMed, bioRxiv) - "These findings illustrate the promise of exploiting FCγRs as a means of IgG entry to target cytosolic proteins and improve human health. RM1mAb and TH5487 synergistically inhibit inflammasome activation in human FCAS PBMCs."

Journal • Genetic Disorders • Inflammation • IL1B • NLRP3

He's Yangchao decoction ameliorates premature ovarian insufficiency by regulating 8-oxoguanine DNA glycosylase 1 in mice (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - "HSYC improves POI by upregulating OGG1 expression, mitigating mtDNA oxidative damage, and inhibiting granulosa cell pyroptosis."

Journal • Preclinical • Oncology • Women's Health • CASP1 • IL1B • OGG1 • TFAM

Inhibition of ogg1 – a novel strategy for treating pulmonary fibrosis OXC-201 reduces inflammation and fibrosis, leading to improved lung function in mice (ERS 2025) - "In this study, pulmonary fibrosis was induced in mice using a chronic bleomycin model, with bleomycin administered twice weekly for four weeks. Additionally, key fibrotic and inflammatory markers were significantly decreased, further supporting its potential as a disease-modifying treatment. These findings highlight OXC-201 as a promising therapeutic candidate for pulmonary fibrosis, offering potential for improved treatment options."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

In vivo antiviral activity of two newly developed compounds reduces the harmful effects of ZIKV in chicken embryos. (PubMed, Biochem Biophys Res Commun) - "Recently, two newly developed compounds, TH5487 and TH6744, have been shown to be antiviral and to reduce the toxic effects of ZIKV on brain organoids...In conclusion, the two compounds tested were nonteratogenic and presented antiviral potential, minimizing the effects caused by ZIKV on brain development. Further tests with other species should be performed to explore the development of these compounds."

Journal • Preclinical • Infectious Disease

TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950. (PubMed, bioRxiv) - "Importantly, these inhibitors block IL-1β secretion in L353P Familial Cold Autoinflammatory Syndrome (FCAS) patient PBMCs where MCC950 fails, demonstrating the therapeutic potential for inflammasome-driven diseases. Together, our findings reveal a novel druggable mechanism of inflammasome inhibition through interference with oxidized DNA sensing and localization, offering new opportunities for treatment of chronic inflammatory disorders."

Journal • Genetic Disorders • Inflammation • Metabolic Disorders • IFNB1 • IL1B • NLRP3

Targeting the NLRP3 inflammasome for inflammatory disease therapy. (PubMed, Trends Pharmacol Sci) - "Although past efforts have focused on inhibiting IL-1β downstream of NLRP3 activation using drugs such as canakinumab, no FDA-approved NLRP3-targeted inhibitors are currently available...In addition, oxidized DNA (oxDNA) has emerged as a key inflammasome trigger, and molecules targeting the pyrin domain have shown promise in inhibiting NLRP3 activation. This review discusses the role of NLRP3 in inflammation-related diseases, the status of ongoing clinical trials, and emerging small-molecule therapeutics targeting NLRP3."

Journal • Review • Alzheimer's Disease • CNS Disorders • Gout • Infectious Disease • Inflammation • Inflammatory Arthritis • Novel Coronavirus Disease • Rheumatology • IL1B • NLRP3

Inhibition by 4-(4-Bromo-2-oxo-3H-benzimidazol-1-yl)-N-(4-iodophenyl)piperidine-1-carboxamide (TH5487) of the Activity of Human 8-Oxoguanine DNA Glycosylase-1 (OGG1) for the Excision of 2,6-Diamino-4-hydroxy-5-formamidopyrimidine, 4,6-Diamino-5-formamidopyrimidine, and 8-Oxoguanine from Oxidatively Damaged DNA. (PubMed, Biochemistry) - "We show that TH5487 efficiently inhibits the excision of both 8-oxo-Gua and FapyGua, and a minor substrate 4,6-diamino-5-formamidopyrimidine (FapyAde) from DNA with the IC50 values of 1.6 μmol/L, 3.1 μmol/L, and 3.1 μmol/L, respectively. The results suggest that the approach used in the present work may be applied for future studies of hOGG1 inhibition by TH5487 on cellular and animal disease models."

Journal • Fibrosis • Immunology • Oncology • Pneumonia • Respiratory Diseases • OGG1

SPORADIC ALZHEIMER'S DISEASE IN A DISH – THE IMPACT OF DNA REPAIR ON PATIENT -DERIVED CEREBRAL ORGANOIDS (ADPD 2025) - " Self-organized cerebral organoids were generated from hiPSCs derived from blood samples from sporadic AD patients and healthy controls and treated with the OGG1 inhibitor TH5487... Sporadic AD patients -derived cerebral organoids are useful to study disease pathology as an alternative to animal models. OGG1 contributes to AD patholog y and modulating its activity might be a promising approach for AD therapy."

Clinical • Alzheimer's Disease • CNS Disorders

Suppression of 8-oxoguanine DNA glycosylase (OGG1) activity produced positive impacts on disease severity, survival, and histopathological features of mice infected with Plasmodium berghei. (PubMed, Exp Parasitol) - "A significant difference in the mean parasitaemia was observed between the Vehicle, TH5487-treated, and O8-treated mice (p<0.001)...The increased survival of treated malaria mice further supported this effect. These findings indicate that OGG1 suppression could be a potential therapeutic strategy during malaria."

Journal • Preclinical • Developmental Disorders • Infectious Disease • Inflammation • Malaria • OGG1

Modulation of 8-Oxoguanine DNA Glycosylase 1 (OGG1) Alleviated Anemia Severity and Excessive Cytokines Release during Plasmodium berghei Malaria in Mice. (PubMed, Iran J Parasitol) - "The findings indicate the involvement of OGG1 in the P. berghei malaria infection. OGG1 inhibition by TH5487 and O8-OGG1 inhibitors suppressed excessive cytokine release, and this may represent a novel therapeutic strategy for ameliorating the severity of malaria infection."

Journal • Preclinical • Anemia • Hematological Disorders • Infectious Disease • Malaria • IFNG • IL10 • IL2 • IL6 • OGG1 • TNFA

The 8-oxoguanine DNA glycosylase-synaptotagmin 7 pathway increases extracellular vesicle release and promotes tumour metastasis during oxidative stress. (PubMed, J Extracell Vesicles) - "Notably, Th5487, the inhibitor of DNA binding activity of OGG1, blocks the recognition and transmission of oxidative signals, alleviates SYT7 expression and suppresses EVs release, thereby preventing tumour progression in vitro and in vivo. Collectively, our study illuminates the significance of 8-oxoG/OGG1/SYT7 axis-driven EVs release in oxidative stress-induced tumour metastasis. These findings provide a deeper understanding of the molecular basis of cancer progression and offer potential avenues for therapeutic intervention."

Journal • Oncology • CDH1 • OGG1

Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy. (PubMed, Mol Med) - "OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis."

Journal • Fibrosis • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • OGG1 • PINK1

Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence. (PubMed, Cell Death Dis) - "Importantly, these results were also recapitulated using specific inhibitors for OGG1 (TH5487) and PARG (PDD00017273). Our results suggest OGG1 and PARG play a fundamental role in the cellular response to CDD and indicate that targeting these enzymes could represent a promising therapeutic strategy for the treatment of head and neck cancers following high-LET radiation."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • OGG1

The potential for OGG1 inhibition to be a therapeutic strategy for pulmonary diseases. (PubMed, Expert Opin Ther Targets) - "Through a synergy of experimental insights gained from cell culture studies and murine models, utilizing prototype OGG1 inhibitors (O8, TH5487, and SU0268), a promising panorama emerges...Thus, the strategic targeting of the active site pocket of OGG1 through the application of small molecules introduces an innovative trajectory for advancing redox medicine. This approach holds particular significance in the context of pulmonary diseases, offering a refined avenue for their management."

Journal • Fibrosis • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • OGG1

Oxcia AB presents positive effects of OXC-201 in lung tissue from patient with Idiopatic Pulmonary Fibrosis (Cision) - "Oxcia presents new preclinical data on OXC-201 at the 7th IPF summit in Boston, September 19-21 and European Respiratory Society (ERS) International Congress 2023 September 9–13. Lung tissue from IPF patients express high levels of several fibrotic biomarkers. Treatment with clinically relevant doses of OXC-201 demonstrated robust dose-dependent reduction of a number of the most important fibrosis-related biomarkers such as TGF-ß and collagen. These data correlate well with results from previous preclinical models, supporting OXC-201 as a potential treatment for IPF."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease

Late Breaking Abstract - Inhibiting OGG1, a new strategy for the treatment of IPF, blocking inflammatory and fibrotic cascades (ERS 2023) - "OXC-201 is a first-in-class small molecule OGG1 inhibitor that has demonstrated proof of concept, and inhibition of pulmonary fibrosis in the bleomycin-induced disease model. The higher doses of OXC-201 reduced the secretion of fibrotic and inflammatory markers to the same or greater degree than that achieved following treatment with Pirfenidone. OXC-201 showed robust and dose-dependent anti-inflammatory and anti-fibrotic efficacy in IPF-PCLuS.; Cell and molecular biology; Endoscopy and interventional pulmonology; Epidemiology; Respiratory intensive care"

Late-breaking abstract • Critical care • Fibrosis • Idiopathic Pulmonary Fibrosis • Inflammation • Transplantation • COL1A1 • CXCL8 • TGFB1 • TIMP1

Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1. (PubMed, Front Immunol) - "In a mouse model of bronchiolitis induced by RSV infection, functional ablation of OGG1 by a small molecule inhibitor (TH5487) enhances IFN-λ production, decreases immunopathology, neutrophilia, and confers antiviral protection. These findings suggest that the ROS-generated epigenetic mark 8-oxoGua via its reader OGG1 serves as a homeostatic thresholding factor in IFN-λ expression. Pharmaceutical targeting of OGG1 activity may have clinical utility in modulating antiviral response."

Epigenetic controller • Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • IRF7 • OGG1

Regulation of the Lung Epithelial Inflammatory Response to Streptococcus Pneumoniae by the DNA Repair Enzyme, 8-Oxoguanine DNA Glycosylase (OGG1) (ATS 2023) - " BEAS-2B lung epithelial cells and primary human lung epithelial cells were transfected with scrambled siRNA or siRNA targeting OGG1 or were treated with the selective active-site inhibitor of OGG1, TH5487, or vehicle control... Epithelial-derived proinflammatory cytokine signaling generated in response to pneumococcal infection is regulated in part through the DNA repair enzyme OGG1. Future work will elucidate if nuclear-localized or mitochondrial-localized OGG1 may have disparate roles on epithelial-derived inflammatory signaling and if modulation of OGG1 may represent a novel therapeutic strategy for S. pneumoniae infection."

Infectious Disease • Inflammation • Pneumococcal Infections • Pneumonia • Pulmonary Disease • Respiratory Diseases • CCL20 • CXCL1 • CXCL8 • IL1B • OGG1

New pre-clinical study shows that OXC-201 may be a promising treatment for IPF (pulmonary fibrosis) (Cisionwire) - "The DNA repair enzyme OGG1 (8-oxoguanine DNA glycosylase-1) has been shown to play an important role in inflammation and fibrosis. The study demonstrates that by genetically knocking out OGG1 or inhibiting the enzyme with OXC-201 (TH5487), acute inflammation and pulmonary fibrosis can be reduced. Administration of OXC-201 to mice with bleomycin-induced pulmonary fibrosis and inflammation markedly reduced lung injury compared to untreated mice....'IPF is a serious disease that has a major impact on quality of life and longevity, which lacks good medical treatment and thus constitutes a major medical need. 'Therefore, it is gratifying that the data presented in the study indicate that OXC-201 has the potential to be developed into a new potent pharmacological treatment of IPF. We are now taking the next step to develop OXC-201 further towards the clinic.'"

Preclinical • Idiopathic Pulmonary Fibrosis • Interstitial Lung Disease

EIC has awarded Oxcia AB a grant of 2.5 million euros within the EIC-Transition program for the development of OXC-201 (Cisionwire) - "Oxcia is very pleased to be able to announce that the EIC (European Innovation Council) has selected Oxcia's OXC-201 as one of the projects receiving grants within the EIC Transition programme. Oxcia receives an amount of 2.5 million euros. EIC is Europe's leading innovation program for identifying, developing and scaling up ground-breaking technologies and innovations. Oxcia is the only Swedish company to receive the grant in this call. OXC-201 is a promising new approach to treating IPF (idiopathic pulmonary fibrosis), with the potential to significantly improve and even halt inflammation and fibrosis. The project is based on new biology published in the scientific journals Science (Visnes et al, Nov 2018) and Nature Communication (Tanner et al, February 2023) and deals with the role of the DNA repair enzyme OGG1 (8-oxo guanine DNA glycosylase) in the regulation of transcription of proinflammatory and profibrotic genes in disease."

Financing • Idiopathic Pulmonary Fibrosis • Interstitial Lung Disease

OGG1 competitive inhibitors show important off-target effects by directly inhibiting efflux pumps and disturbing mitotic progression. (PubMed, Front Cell Dev Biol) - "It is thus critical to consider these previously unreported non-specific effects when interpreting studies using TH5487 and SU0268 in the context of OGG1 inhibition. Additionally, our work highlights the persistent need for new specific inhibitors of the enzymatic activity of OGG1."

Journal • Oncology • ABCB1

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model. (PubMed, Nat Commun) - "IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms...In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis...OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required."

Journal • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Metabolic Disorders • Pneumonia • Pulmonary Disease • Respiratory Diseases • OGG1 • SMAD7