setanaxib (GKT831) / Calliditas, National Institutes of Health - LARVOL DELTA

Aβ40 Improves Cerebrovascular Endothelial Function via NOX4-Dependent Hydrogen Peroxide Release. (PubMed, Int J Mol Sci) - "Aβ40-induced H2O2 production was attenuated in the presence of the pan-NOX inhibitor, apocynin, or the NOX1/4-selective inhibitors, setanaxib and GKT136901. Since only the NOX4 isoform is expressed in bEnd.3 cells, these results indicate that NOX4 is responsible for the release of H2O2 stimulated by Aβ40. Taken together, the present study demonstrated that Aβ40 peptide exerts beneficial effects in bEnd.3 endothelial cells via the NOX4-dependent mechanism."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • NOX4

A Study to Evaluate Setanaxib in Patients With Alport Syndrome (clinicaltrials.gov) - P1/2 | N=19 | Completed | Sponsor: Calliditas Therapeutics AB | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders

Advancing care in primary biliary cholangitis: emerging insights and novel therapies. (PubMed, Expert Opin Pharmacother) - "Ursodeoxycholic acid (UDCA) has been the mainstay of therapy for over 40 years...Notably, seladelpar and elafibranor, two selective agonists of peroxisome proliferator-activated receptors, achieved high rates of biochemical response and good tolerability, leading to their recent approval for second-line treatment of PBC...- Personalized treatment approaches for PBC are both feasible and essential to improve biochemical response, extend transplant-free survival and alleviate symptom burden. Well-tolerated novel therapies are poised to reshape the treatment landscape in the near future."

Journal • Review • Cholestasis • Dermatology • Fatigue • Fibrosis • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus • Transplantation

Dual inhibition of oxidative phosphorylation and glycolysis using a hyaluronic acid nanoparticle NOX inhibitor enhanced response to radiotherapy in colorectal cancer. (PubMed, Biomaterials) - "Furthermore, the combined therapy increased intratumoral infiltration of activated cytotoxic T cells and M1 macrophages but reduced the levels of immunosuppressive fibroblasts and M2 macrophages. Our results support HANP/GKT831 as a cancer nanotherapeutic agent that induces redox and bioenergy stresses in cancer cells for enhanced therapeutic response to radiotherapy."

Journal • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor

NOX4-driven Mitochondrial Oxidative Stress in Aging Promotes Myocardial Remodeling and Increases Susceptibility to Ventricular Tachyarrhythmia. (PubMed, Free Radic Biol Med) - "Treatment with Setanaxib, a NOX1/NOX4 inhibitor, or co-expression of mitochondrial catalase in Nox4TG (Nox4TG+mCAT) mice, mitigated fibrosis, reduced inflammation, and protected against VT. These findings suggest that mitochondrial NOX4 overexpression promotes VT through electrical remodeling and pro-arrhythmogenic structural changes despite RyR2 oxidation and dysfunction. In conclusion, aging-related NOX4-driven mitochondrial oxidative stress increases the risk of VT by promoting changes in the electrical and structural properties of the myocardium, highlighting potential therapeutic strategies that target NOX4 in cardiac pathologies associated with aging."

Journal • Cardiovascular • Fibrosis • Immunology • Inflammation • Ventricular Tachycardia • CAT • MKI67 • NOX4 • TGFB1

Reduced glutathione enhances adipose tissue-derived mesenchymal stem cell engraftment efficiency for liver fibrosis by targeting TGF(31/SMAD3/NOX4 pathway (APASL 2025) - " Liver fibrotic mice were administrated with GSH, setanaxib (a NOX4 inhibitor) and SIS3 (a TGFβ/SMAD3 pathway inhibitor) during ADSC transplantation... GSH could improve the engraftment efficiency of ADSCs in liver fibrosis by targeting TGFβ1/SMAD3/NOX4 signaling pathway, which provides a new theoretical basis for GSH enhancing ADSC engraftment efficiency in liver diseases."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • NOX4 • SMAD3

Reduced glutathione enhances adipose tissue-derived mesenchymal stem cell engraftment efficiency for liver fibrosis by targeting TGFβ1/SMAD3/NOX4 pathway. (PubMed, Bioeng Transl Med) - "Liver fibrotic male mice were administrated GSH, setanaxib (STX), and SIS3 during ADSC transplantation...More importantly, GSH enhanced the therapeutic efficacy of ADSC therapy in liver fibrotic mice. Taken together, GSH could improve the engraftment efficiency of ADSCs in liver fibrosis by targeting TGFβ1/SMAD3/NOX4 signaling pathway, which provides a new theoretical basis for GSH enhancing ADSC engraftment efficiency in liver diseases."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Transplantation • NOX4 • SMAD3 • TGFB1

Safety and Efficacy of Oral GKT137831 in Patient With Type 2 Diabetes and Albuminuria (clinicaltrials.gov) - P2 | N=136 | Completed | Sponsor: Calliditas Therapeutics AB | N=200 ➔ 136

Enrollment change • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

A Study to Evaluate Setanaxib in Patients With Alport Syndrome (clinicaltrials.gov) - P1/2 | N=18 | Active, not recruiting | Sponsor: Calliditas Therapeutics AB | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders

A Study to Evaluate Setanaxib in Patients With Alport Syndrome (clinicaltrials.gov) - P1/2 | N=18 | Active, not recruiting | Sponsor: Calliditas Therapeutics AB | Trial completion date: Jan 2025 ➔ Jun 2025 | Trial primary completion date: Jan 2025 ➔ May 2025

Trial completion date • Trial primary completion date • Genetic Disorders

6-Nitrodopamine is an endogenous mediator of rat seminal vesicles contractility. (PubMed, Andrology) - "This is the first demonstration that epithelial-derived 6-ND modulates rat seminal vesicle contractility."

Journal • Preclinical • NOS3

Mitochondrial Transcriptional-Translational Conflict Contributes to Defective Erythropoiesis and Disease Progression in Splicing Factor Mutant Myelodysplastic Syndromes (ASH 2024) - "We screened ROS scavengers (N-acetylcysteine), NAD+ precursor (Nicotinamide Riboside), integrated stress response inhibitor or ESR inhibitor (ISRIB, 4-Phenylbutyric acid), NADPH oxidase inhibitor (Setanaxib), tropomyosin receptor kinase (TRK) inhibitor (Larotrectinib), and translation-associated drugs (A-484954, 4EGI-1) to test whether they can rescue anemia, but unfortunately all of these drugs failed to improve erythropoiesis of mutated cells. In summary, our findings provide insights into the critical role of mitochondrial transcription and translation in governing erythropoiesis via the mTOR signaling pathway. We propose that SF3B1 mutation cause dysfunctional mitochondria and elevated ESR, leading to aberrant mitochondrial translation and impaired protein synthesis, and suggest rapamycin as a potential therapeutic strategy for MDS patients with SF3B1 mutation to alleviate anemia by inhibiting stress-induced mTOR activation."

Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ATF4 • CD34 • SF3B1

GKT137831 in IPF Patients with Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2 | N=58 | Completed | Sponsor: University of Alabama at Birmingham | Recruiting ➔ Completed

Trial completion • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

LRRC8A drives NADPH oxidase-mediated mitochondrial dysfunction and inflammation in allergic rhinitis. (PubMed, J Transl Med) - "LRRC8A drives the upregulation of NOX1, NOX4, and p22phox, leading to ROS overproduction and mitochondrial dysfunction. It also activates NF-κB, ultimately leading to nasal mucosal epithelial inflammation. LRRC8A may be a potential target for the treatment of AR."

Journal • Allergic Rhinitis • Immunology • Inflammation • Metabolic Disorders • IL13 • IL4 • IL5 • LRRC8A • NOX4

Kirenol Ameliorates Myocardial Ischemia-Reperfusion Injury by Promoting Mitochondrial Function and Inhibiting Inflammasome Activation. (PubMed, Cardiovasc Drugs Ther) - "This study demonstrates that Kirenol mitigates myocardial I/R injury by inhibiting NOX1 and NOX4, restoring mitochondrial function, and ameliorating macrophage pyroptosis."

Journal • Cardiovascular • Inflammation • Myocardial Ischemia • Reperfusion Injury • NOX4

Nox4 is involved in acute kidney injury associated to intravascular hemolysis. (PubMed, Free Radic Biol Med) - "We also evaluated whether nephrotoxic effects of heme may be reduced by using Nox4 siRNA and pharmacologic inhibition with GKT137831, a Nox4 inhibitor, both in vivo and in cultured renal cells...Our data identify Nox4 as a key enzyme involved in intravascular hemolysis-induced AKI. Thus, Nox4 inhibition may be a potential therapeutic approach to prevent renal damage in patients with severe hemolytic crisis."

Journal • Acute Kidney Injury • Hematological Disorders • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • NOX4

Setanaxib plus pembrolizumab for the treatment of recurrent or metastatic squamous cell carcinoma of the head & neck: Results of a randomized, double-blind phase II trial (ESMO 2024) - P2 | "STX added to PMB showed statistically significant effects on PFS and OS in pts with rmHNSCC. STX was well tolerated. This combination could have utility in targeting myCAF-rich, 'immune-excluded' tumours.;"

Clinical • IO biomarker • Metastases • P2 data • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CAFs • CD8 • NOX4

NADPH oxidase 1/4 dual inhibitor setanaxib suppresses platelet activation and thrombus formation. (PubMed, Life Sci) - "This study is the first to show that setanaxib suppresses ROS generation, platelet activation, and collagen-induced thrombus formation, suggesting its potential use in treating thrombotic or cardiovascular diseases."

Journal • Cardiovascular • Hematological Disorders • Thrombosis • PLCG2 • SYK • VAV1

A Study of Setanaxib Co-Administered With Pembrolizumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of Head and Neck (SCCHN) (clinicaltrials.gov) - P2 | N=55 | Active, not recruiting | Sponsor: Calliditas Therapeutics Suisse SA | Trial completion date: Sep 2024 ➔ Nov 2025

Metastases • Trial completion date • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Calliditas announces positive TRANSFORM Phase 2b topline data in primary biliary cholangitis (PRNewswire) - P2b | N=76 | TRANSFORM (NCT05014672) | Sponosr: Calliditas Therapeutics Suisse SA | "Calliditas Therapeutics AB...today announced that the Phase 2b TRANSFORM trial met its primary endpoint, showing statistically significant improvement in ALP (Alkaline Phosphatase) for both doses tested versus placebo...Patients treated with setanaxib showed statistically significant improvements in the primary endpoint of ALP of 19% in the 1600mg arm and 14% in the 1200mg arm and showed positive trends on liver stiffness assessed by FibroScan at 24 weeks. Setanaxib treatment was generally well tolerated with overall number of TEAEs (treatment emergent adverse events), as well as serious TEAEs, being similar between active treatment and placebo...The company is conducting additional clinical trials with setanaxib and is expecting the investigator led Phase 2 trial in IPF (idiopathic pulmonary fibrosis) to provide top line data in Q4 2024 / Q1, 2025."

P2 data • P2b data • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Primary Biliary Cholangitis • Respiratory Diseases

TRANSFORM: A Trial of Setanaxib in Patients With Primary Biliary Cholangitis (PBC) and Liver Stiffness (clinicaltrials.gov) - P2 | N=76 | Completed | Sponsor: Calliditas Therapeutics Suisse SA | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Immunology • Primary Biliary Cholangitis

Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging. (PubMed, Front Immunol) - "In aged Apoe-/- mice, inhibition of NOX4 activity using GKT137831 significantly reduced macrophage mitochondrial ROS and improved mitochondrial function, resulting in decreased CD68+CD80+ and increased CD163+CD206+ lesion macrophage proportion and attenuated atherosclerosis. Our findings suggest that increased NOX4 in aging drives macrophage mitochondrial dysfunction, glycolytic metabolic switch, and pro-inflammatory phenotype, advancing atherosclerosis. Inhibiting NOX4 or mitochondrial dysfunction could alleviate vascular inflammation and atherosclerosis, preserving plaque integrity."

IO biomarker • Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • Metabolic Disorders • APOE • CD163 • CD38 • CD68 • CD80 • IFNG • IL1B • IL4 • MRC1 • NOX4

Particulate Matter-Induced Neurotoxicity: Unveiling the Role of NOX4-Mediated ROS Production and Mitochondrial Dysfunction in Neuronal Apoptosis. (PubMed, Int J Mol Sci) - "The cytotoxic effects induced by PMs were alleviated by NOX inhibitors GKT137831 and Apocynin...Variability in NADPH oxidase sources underscores the complexity of PM-induced neurotoxicity. Our findings highlight NOX4-driven ROS and mitochondrial dysfunction, suggesting a potential therapeutic approach for mitigating PM-induced neurotoxicity."

IO biomarker • Journal • CNS Tumor • Metabolic Disorders • Neuroblastoma • Oncology • Solid Tumor • BAX • BCL2 • CASP3 • NOX4 • VDAC1

Calliditas provides setanaxib patent update (PRNewswire) - "Calliditas Therapeutics AB...announced that the United States Patent and Trademark Office (USPTO) has issued a patent for application no. 16/760,910 entitled 'Use of NOX Inhibitors for Treatment of Cancer'. The patent covers a method of treating a solid tumor presenting resistance to PD-1 inhibitor immunotherapy by administering setanaxib in combination with a PD-1 inhibitor. The patent will have an expiration date in 2039."

Patent • Oncology • Solid Tumor

Autophagy caused by oxidative stress promotes TGF-β1-induced epithelial-to-mesenchymal transition in human peritoneal mesothelial cells. (PubMed, Cell Death Dis) - "Treatment with GKT137831 (20 μM), a NOX1/4 inhibitor, reduced ROS in the mitochondria of HPMC cells and reduced TGF-β1-induced mitochondrial damage...Direct inhibition of autophagy and its indirect inhibition through the reduction of mitochondrial damage by upstream NOX4 inhibition reduced EMT in HPMCs. These results suggest that autophagy could serve as a therapeutic target for the prevention of peritoneal fibrosis in patients undergoing peritoneal dialysis."

Journal • Fibrosis • Immunology • NOX4 • SMAD2 • SMAD4 • TGFB1