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

Inhibition of NOX4 attenuates muscle damage and mitochondrial dysfunction in inflammatory myopathy. (PubMed, Arthritis Res Ther) - "We showed that NOX4 is associated with muscle damage in IIM and suggest that its inhibition may have novel therapeutic effect for mitigating muscle damage and disease progression in IIM."

Journal • Immunology • Inflammation • Metabolic Disorders • Myositis • IFNG • IL6 • MYOD1 • NOX4

Pyraclostrobin induces brain oxidative stress, apoptosis and inflammation through mitochondrial phosphorylation-induced ROS activation of the p38 MAPK pathway. (PubMed, Pestic Biochem Physiol) - "NAC and GKT137831 blocked ROS-mediated MAPK signaling. JC-1 and DHE staining experiments further demonstrate that PY causes mitochondrial dysfunction in the mouse brain and significantly increases ROS production. Collectively, these findings enhance our understanding of the neurotoxic effects of PY pesticide residues and provide a scientific foundation management."

IO biomarker • Journal • CNS Disorders • Inflammation • Metabolic Disorders • Vascular Neurology • BCL2 • CASP3 • CASP8 • CASP9 • IL10 • IL1B • IL6 • TNFA

From RAAS blockade to regenerative medicine: evolving treatment strategies in Alport syndrome. (PubMed, Pediatr Nephrol) - "Adjunctive commercially available metabolic modulators, including SGLT2i, mineralocorticoid receptor antagonists, ezetimibe and GLP-1 receptor agonists, may offer additional kidney protection. Ameliorating therapies being tested in Phase II trials include endothelin receptor antagonists (e.g., atrasentan), dual endothelin receptor antagonist and angiotensin II receptor inhibition (e.g., sparsentan) FXR agonists (e.g., vonafexor), inducers of cholesterol efflux (e.g., VAR200 and R3R01), and NOX1/4 inhibitors (e.g., setanaxib), several of which are currently being evaluated in clinical trials. Novel strategies such as exon skipping, gene editing, and nonsense mutation readthrough (e.g., ELX-02) are advancing toward precision medicine approaches as disease modifying agents targeting the genetic cause of AS...This review summarizes the current landscape of AS classification and treatment, highlighting both standard interventions and experimental therapies. Emphasis is placed..."

Journal • Review • Fibrosis • Gene Therapies • Genetic Disorders • Glomerulonephritis • Immunology • Renal Disease • COL4A5

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

Safety and Preliminary Efficacy Findings from a Phase 2A Randomized, Double-Blind, Placebo-Controlled Trial of Setanaxib in Patients with Alport Syndrome (KIDNEY WEEK 2025) - P1/2 | "There was a 5% mean reduction in eGFR with seta vs pbo at 24 wks and a 4% reduction at 4 wks post dosing. Conclusion In pts with AS, setanaxib plus background therapy had an acceptable safety profile with a trend towards UPCR reduction after 24 wks of dosing and at 4 wks post dosing vs background therapy alone."

Clinical • Late-breaking abstract • P2a data • Fibrosis • Gastroenterology • Genetic Disorders • Hepatology • Immunology

Basal release of 6-cyanodopamine in human vas deferens, a new endogenous catecholamine that enhances smooth muscle contractility. (PubMed, Eur J Pharmacol) - "Basal release of 6-CYD was quantified by liquid chromatography coupled to tandem mass spectrometry in the absence and presence of either the voltage-gated sodium channel blocker tetrodotoxin or the dual NADPH oxidase NOX1,4 inhibitor GKT137831. The results indicate that epithelium 6-CYD is an endogenous mediator of HEVD contractility. Whether NADPH oxidases are involved in 6-CYD biosynthesis remains to be further investigated."

Journal

Mitochondrial NOX4 Drives Atrial Fibrillation via Redox-Dependent Structural Remodeling and Fibrosis. (PubMed, Free Radic Biol Med) - "Inhibiting NOX4 with Setanaxib reduced AF duration. These findings demonstrate that mitochondrial NOX4 promotes AF not by altering ionic currents or promoting RyR2 leak, but through redox-sensitive fibrotic remodeling. Our results underscore the chamber-specific consequences of oxidative stress and support therapeutic targeting of mitochondrial NOX4 to mitigate atrial remodeling and AF in aging hearts."

Journal • Atrial Fibrillation • Cardiovascular • Fibrosis • Immunology • CAPN2 • NOX4 • POSTN

Genetic and Pharmacological Inhibition of NOX4 Protects Against Rhabdomyolysis-Induced Acute Kidney Injury Through Suppression of Endoplasmic Reticulum Stress. (PubMed, Antioxidants (Basel)) - "We applied renal tubular epithelial cell (RTEC)-specific NOX4 knockout and the NOX4 inhibitor GKT137831 to treat RIAKI in vivo and in vitro...Collectively, these findings demonstrate that genetic and pharmacological suppression of NOX4 protects against RIAKI by reducing ROS generation, boosting antioxidant defense and inhibiting ERS activation. NOX4 inhibition may offer a potential approach for developing new treatment options for RIAKI."

Journal • Acute Kidney Injury • Inflammation • Nephrology • Renal Disease • NOX4

An update on novel investigational agents for the treatment of primary biliary cholangitis. (PubMed, Expert Opin Investig Drugs) - "While ursodeoxycholic acid (UDCA) remains the first-line treatment, up to 40% of patients show an inadequate response...Obeticholic acid (OCA), a farnesoid X receptor agonist, was initially approved but recently lost its marketing authorization in the EU due to an unfavorable risk-benefit balance. Fibrates, particularly bezafibrate and fenofibrate, have shown promising results in improving biochemical markers and reducing pruritus, although they remain off-label. We here focus on new FDA- and EMA-approved therapies, including the PPAR agonists elafibranor and seladelpar, which demonstrate improved biochemical response and, in the case of seladelpar, a significant reduction in pruritus. Additional investigational agents include NOX inhibitors such as setanaxib, IBAT inhibitors like linerixibat and odevixibat, and golexanolone, targeting fatigue through modulation of GABAergic neurotransmission. Despite advances, challenges remain in treatment personalization, access to..."

Journal • Review • Dermatology • Fatigue • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Primary Biliary Cholangitis • Pruritus

Targeting NOX1/4-YAP/TEAD-CD47 Axis Promotes Macrophage Phagocytosis and Potentiates Radiotherapy Antitumor Efficacy in NSCLC (IASLC-WCLC 2025) - "THP-1-derived macrophages were co-cultured with lung tumor cells treated with NOX1/NOX4 inhibitor (GKT137831, GKT)...Conclusions : This study unveils a novel mechanism which regulates basal CD47 expression and radiotherapy-induced CD47 upregulation in tumor cells. Targeting NOX1/NOX4-YAP1/TEAD4 signaling could suppress CD47 expression, resulting in promoting phagocytosis function of macrophages without blood toxicity and improving the anti-tumor efficacy of radiotherapy in NSCLC."

Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD47 • NOX4 • TEAD4 • YAP1

GSN000400: 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 | Completed | Sponsor: Calliditas Therapeutics Suisse SA | Active, not recruiting ➔ Completed

IO biomarker • Trial completion • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CAFs • PD-L1

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

Synthetic and semi-synthetic antioxidants in medicine and food industry: a review. (PubMed, Front Pharmacol) - "Nevertheless, some compounds, such as ebselen, edaravone, MitoQ10, and potentially N-acetylcysteine, have shown promising results...One emerging therapeutic strategy involves inhibition of NADPH oxidase (NOX) enzymatic activity, with compounds such as ebselen, S17834, and GKT137831 showing potential across various disease models...Despite extensive research, only a few synthetic antioxidants, such as edaravone, are currently used in clinical practice. Currently, no new antioxidant drugs are expected to receive regulatory approval in the near future."

Journal • Review

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

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

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