norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis

Journal article

Background & Aim Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 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 (500 mg/d, 1,000 mg/d or 1,500 mg/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 1,500 mg/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 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/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.

Authors: Fickert, P; Hirschfield, G; Denk, G; Marschall, H; Altorjay, I

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Journal of Hepatology
• Volume: 67
• Issue: 3
• Pages: 549-558
• Publication date: 2017-05-18
• Acceptance date: 2017-05-06
• DOI: 10.1016/j.jhep.2017.05.009
• EISSN: 1600-0641
• ISSN: 0168-8278
• Pmid: 28529147
• Language: English
• Keywords: side chain-shortened bile acids; cholestasis; alkaline phosphatase; ursodeoxycholic acid; sclerosing cholangitis; cholehepatic shunting; bile acid treatment