norucholic acid (norUDCA) / Dr Falk, Eisai - LARVOL DELTA

Norucholic acid for the treatment of primary sclerosing cholangitis: 96-week analysis of a pivotal phase 3 trial (EASL 2025) - "No reproduction, re-use or transcription for any commercial purpose or use of the content is permitted without the written permission of the authors. Permission for re-use must be obtained directly from the authors."

Late-breaking abstract • P3 data • Hepatology

Treatment of grafts not meeting criteria for transplantation with nor-ursodeoxycholic acid during normothermic machine perfusion reduces apoptosis and biliary injury markers (EASL 2025) - No abstract available

Hepatology • Transplantation

Treatment of grafts not meeting criteria for transplantation with nor-ursodeoxycholic acid during normothermic machine perfusion reduces apoptosis and biliary injury markers (EASL 2025) - "The present data suggests an anti-apoptotic effect as well as an improvement in bile compostition after treatment of extended criteria donor grafts with norUDCA during NMP. NorUDCA might be able to ameliorate the detrimental effects of bile toxicity on the ischemia-injured biliary tree. Therefore, therapeutic application of norUDCA prior to transplantation seems promising, especially for liver grafts at risk for biliary complications."

IO biomarker • Cardiovascular • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Transplantation • BCL2 • CASP3

Active transport via bile salt export pump (Bsep/Abcb11) is not required for cholehepatic shunting and choleretic actions of Norucholic acid (NCA/norUDCA) in mice (EASL 2025) - "Our data indicate that transport via Bsep/Abcb11 is not essential for choleretic effects of unconjugated NCA. In contrast, transport of taurine-conjugated NCA into bile requires Bsep/Abcb11."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • ABCB1 • ABCC3

24-Nor-ursodeoxycholic acid: a novel treatment targeting T-cell-mediated immune dysregulation in primary sclerosing cholangitis and beyond. (PubMed, Gut) - No abstract available

Journal • Hepatology

Study with Norucholic Acid Tablets in Patients with Primary Sclerosing Cholangitis (PSC) (clinicaltrials.gov) - P3 | N=120 | Not yet recruiting | Sponsor: Dr. Falk Pharma GmbH

New P3 trial • Hepatology

Bile acid therapy for primary biliary cholangitis: Pathogenetic validation. (PubMed, World J Exp Med) - "In addition to UDCA, the use of obeticholic acid, tauroursodeoxycholic acid and norursodeoxycholic acid as drugs is discussed. The pathogenetic rationale for treatment of PBC with various bile acid drugs is discussed in this review. Emphasis is made on the mechanisms explaining the beneficial therapeutic effects and potential of each of the bile acid as a drug, based on the understanding of the pathogenesis of the initial stages of PBC."

Journal • Review • Cholestasis • Developmental Disorders • Hepatology • Immunology • Primary Biliary Cholangitis

Primary sclerosing cholangitis. (PubMed, Nat Rev Dis Primers) - "Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival."

Journal • Review • Cholangiocarcinoma • Cholestasis • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Inflammatory Bowel Disease • Oncology • Transplantation • CCR2 • FGF19

24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting TH17 pathogenicity and transdifferentiation. (PubMed, Gut) - "NorUDCA restricts TH17 inflammation in multiple mouse models, potentiating future clinical applications for treating TH17-mediated intestinal diseases and beyond."

Journal • Cholestasis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • CD4 • IL17A

norUrsodeoxycholic Acid vs Placebo in PSC (clinicaltrials.gov) - P3 | N=303 | Active, not recruiting | Sponsor: Dr. Falk Pharma GmbH | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2023 ➔ Jun 2026 | Trial primary completion date: Apr 2021 ➔ Jan 2025

Enrollment closed • Trial completion date • Trial primary completion date • Hepatology

Nor-Ursodeoxycholic Acid Improves Biliary Markers during Normothermic Machine Perfusion (IHPBA 2024) - "NorUDCA seems to have a similar effect on bile production during NMP compared to preclinical data. It might be able to ameliorate the detrimental effects of bile on the damaged biliary tree after ischemia. Its diverse therapeutic effects make it an immensely promising agent for application during NMP in the context of liver transplantation."

Cardiovascular • Fibrosis • Hepatology • Transplantation

Therapeutic Application of Norursodeoxycholic Acid in Normothermic Machine Perfusion Reduces Perfusate Apoptosis Markers in Livers Rejected for Transplantation (IHPBA 2024) - "The present data suggests an anti-apoptotic effect of norUDCA during NMP of ECD liver grafts in a preclinical model. Use of norUDCA during NMP might be relevant for further improvement of outcome after liver transplantation."

IO biomarker • Fibrosis • Hepatology • Metabolic Disorders • Transplantation • BCL2 • CASP3

A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway. (PubMed, Hepatol Commun) - "We developed a novel model to study the reactive cholangiocyte state in response to pathological stimuli in cholestasis and demonstrated a contributory role of S1PR2 signaling in both injury and NorUDCA/UDCA treatments. This model is a valuable tool to further explore the pathophysiology of human cholangiopathies."

Journal • Cholestasis • Hepatology • TNFA

Norursodeoxycholic Acid vs. Placebo in NASH (clinicaltrials.gov) - P2 | N=363 | Recruiting | Sponsor: Dr. Falk Pharma GmbH | Phase classification: P2b ➔ P2

Phase classification • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

Targeting bile salt homeostasis in biliary diseases. (PubMed, Curr Opin Gastroenterol) - "Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future."

Journal • Cholestasis • Hepatology • Immunology • Primary Biliary Cholangitis • ANXA1 • ANXA11

A NOVEL MODEL TO STUDY MECHANISMS OF CHOLESTASIS IN HUMAN CHOLANGIOCYTES REVEALS A ROLE FOR THE SIPR2 PATHWAY (AASLD 2023) - "We modeled the reactive state in human ECOs. In response to cholestatic conditions we demonstrated a contributory role of S1PR2 in injury and therapeutic response via NorUDCA and UDCA. This new cholangiocyte injury model provides a valuable tool to further understand the role of bile acids in human cholangiopathies."

Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • CXCL8 • MT-CO2 • TGFB1 • VIM

24-Norursodeoxycholic acid ameliorates experimental alcohol-related liver disease and activates hepatic PPARγ. (PubMed, JHEP Rep) - "In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option."

Journal • Cholestasis • Hepatology • Liver Failure • Oncology • IL10 • IL1B • IL6 • PPARG

Current Therapeutics in Primary Sclerosing Cholangitis. (PubMed, J Clin Transl Hepatol) - "Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy."

Journal • Review • Biliary Cancer • Cholangiocarcinoma • Colorectal Cancer • Fibrosis • Gastrointestinal Cancer • Hepatology • Metabolic Disorders • Oncology • Solid Tumor • Transplantation

Norursodeoxycholic Acid vs. Placebo in NASH (clinicaltrials.gov) - P2b | N=363 | Recruiting | Sponsor: Dr. Falk Pharma GmbH | Trial completion date: Apr 2022 ➔ Apr 2025 | Trial primary completion date: Apr 2022 ➔ Jan 2025

Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Steatohepatitis

Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice. (PubMed, JCI Insight) - "The results indicate that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease."

Journal • Preclinical • Gastroenterology • Hepatology

BENEFICIAL EFFECTS OF UDCA AND NORUDCA IN A RODENT MODEL OF STEATOSIS ARE LINKED TO MODULATION OF GPBAR1 SIGNALING (AASLD 2022) - "UDCA and norUDCA have shown various degrees of activity in a rodent model of steatosis and their beneficial effects are linked to GPBAR1 signaling modulation."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Primary Biliary Cholangitis

MONITORING TREATMENT RESPONSE OF NOR-URSODEOXYCHOLIC ACID IN Mdr2 (Abcb4)-/- MICE WITH AUTOMATED SHEAR WAVE ELASTOGRAPHY (AASLD 2022) - "These results demonstrate that longitudinal in vivo SWE imaging in a genetic model of cholestatic fibrosis is feasible and can distinguish differences in pathological severity between sexes and treatment regimens. Future work will explore utilizing this technology for predicting drug response and applicability as an endpoint for mouse drug trials."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Oncology • ABCB4

Primary biliary cholangitis as a roadmap for the development of novel treatments of cholestatic liver diseases. (PubMed, J Hepatol) - "Obeticholic acid is currently the only approved second line therapy for PBC. Drugs in the late phase of clinical development are the PPAR agonists, NorUDCA and the NOX 1&4 inhibitors."

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

Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling. (PubMed, Biochim Biophys Acta Mol Cell Biol Lipids) - "In contrast norUDCA is poorly metabolized exerting a minimal impact on GPBAR1 signaling. Together, these data, highlight the potential role of UDCA and norUDCA in treating of NAFLD, though these beneficial effects are supported by different mechanisms."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

24-Norursodeoxycholic acid ameliorates experimental alcoholic liver disease in both preventive and therapeutic settings (EASL-ILC 2022) - "NorUDCA ameliorates hepatic inflammation and steatosis in experimental ALD and could serve as a therapeutic agent for ALD in the future."

Hepatology • Immunology • Inflammation • Liver Failure • IL10 • IL1B • IL6 • PPARG • TNFA