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norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis
Open accessAbstract
BACKGROUND & AIM: homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC. METHODS: One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. RESULTS: norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. CONCLUSIONS: norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507.
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“Clinically, norUDCA improved biochemical markers of cholestasis in a recent phase 2 clinical trial in PSC irrespective of prior exposure and response to UDCA212”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [212]
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Metadata
- Authors
- Fickert, P., Hirschfield, G. M., Denk, G., Marschall, H.-U., Altorjay, I., Färkkilä, M., Schramm, C., Spengler, U., Chapman, R., Bergquist, A., Schrumpf, E., Nevens, F., Trivedi, P., Reiter, F. P., Tornai, I., Halilbasic, E., Greinwald, R., Pröls, M., Manns, M. P., & Trauner, M.
- Affiliations
- Medical University of Graz (AT)
- University of Birmingham (GB)
- LMU Klinikum (DE)
- University of Gothenburg (SE)
- University of Helsinki (FI)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Bonn (DE)
- John Radcliffe Hospital (GB)
- Karolinska University Hospital (SE)
- Oslo University Hospital (NO)
- KU Leuven (BE)
- Medical University of Vienna (AT)
- Dr Falk Pharma (Germany) (DE)
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Trauner, Michael
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 67
- Issue
- 3
- Pages
- 549-558
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2616282068
- Cited by
- 297
- References
- 45
- Citations by year
- 2026: 30 · 2025: 22 · 2024: 38 · 2023: 25 · 2022: 35 · 2021: 43 · 2020: 36 · 2019: 29 · 2018: 28 · 2017: 9
- FWCI
- 17.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, cc-by-nc-nd)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc-nd)
- Funders
- Falk Foundation
- Pfizer
- Gilead Sciences
- National Institute for Health and Care Research
- Astellas Pharma
- Dr. Falk Pharma
- Cilag
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Keywords
- primary sclerosing cholangitis, cholestasis, alkaline phosphatase, dose-dependent effects, safety profile, pruritus, liver fibrosis
- MeSH terms
- Adult, Alkaline Phosphatase, Cholestasis, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Ursodeoxycholic Acid, Cholangitis, Sclerosing
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