Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial
Abstract
Background Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease.Methods We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38.Findings Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change -27·8%, 95% repeated CI -34·7 to -14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).Interpretation Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies.Funding Dr Falk Pharma GmbH.
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Norucholic acid has shown anticholestatic, anti-inflammatory and anti-fibrotic properties in preclinical models and is being tested for MASH with initial results showing improvement in ALT and liver steatosis.
“A synthetic UDCA derivative, 24norursodeoxycholic acid (norucholic acid), has shown anticholestatic, anti-in fl ammatory and anti- fi brotic properties in preclinical models 376 and is being tested for MASH with initial results showing improvement in ALT and liver steatosis.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [377]
norUDCA is a promising therapeutic agent in NAFLD/NASH with first encouraging phase 2a data.
“making it a promising therapeutic agent in NAFLD/NASH with first encouraging phase 2a data215”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [215]
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- Authors
- Traussnigg, S., Schattenberg, J. M., Demir, M., Wiegand, J., Geier, A., Teuber, G., Hofmann, W. P., Kremer, A. E., Spreda, F., Kluwe, J., Petersen, J., Boettler, T., Rainer, F., Halilbasic, E., Greinwald, R., Pröls, M., Manns, M. P., Fickert, P., Trauner, M., Vogel, W., Aigner, E., Datz, C., Tilg, H., Gerken, G., Rust, C., Cordes, H.-J., Steib, C., Pathil-Warth, A., Prinz, M., Lammert, F., Antoni, C., Klausmann, G., Häussinger, D., & Zipprich, A.
- Affiliations
- Medical University of Vienna (AT)
- Johannes Gutenberg University Mainz (DE)
- University Hospital Cologne (DE)
- Leipzig University (DE)
- Universitätsklinikum Würzburg (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Asklepios Klinik St. Georg (DE)
- University of Freiburg (DE)
- Medical University of Graz (AT)
- Dr Falk Pharma (Germany) (DE)
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Trauner, Michael
- ORCID
- Traussnigg, Stefan
- Schattenberg, Jörn M
- Demir, Münevver
- Wiegand, Johannes
- Geier, Andreas
- Hofmann, Wolf Peter
- Kremer, Andreas E
- Kluwe, Johannes
- Boettler, Tobias
- Rainer, Florian
- Halilbasic, Emina
- Manns, Michael P
- Fickert, Peter
- Trauner, Michael
- Aigner, Elmar
- Datz, Christian
- Tilg, Herbert
- Gerken, Guido
- Steib, Christian
- Lammert, Frank
- Häussinger, Dieter
- Zipprich, Alexander
- Venue
- The Lancet Gastroenterology & Hepatology
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 4
- Issue
- 10
- Pages
- 781-793
- ISSN
- 2468-1156 (ISSN-L)
- 2468-1253
- OpenAlex
- W2964269168
- Cited by
- 88
- References
- 26
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 10 · 2023: 19 · 2022: 11 · 2021: 17 · 2020: 10 · 2019: 4
- FWCI
- 7.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet. Gastroenterology & hepatology (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Funders
- Dr. Falk Pharma
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- non-alcoholic fatty liver disease, dose-finding, alanine aminotransferase, liver fibrosis, diabetes mellitus, hepatoprotection, bile acid therapy, adverse events, dose-dependent effects, steatosis, liver enzymes, antifibrotic effect, treatment-emergent adverse events
- MeSH terms
- Adult, Alanine Transaminase, Aspartate Aminotransferases, Blood Glucose, Cholagogues and Choleretics, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Lipids, Male, Middle Aged, Ursodeoxycholic Acid, Treatment Outcome, Non-alcoholic Fatty Liver Disease
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