norUrsodeoxycholic Acid Improves Cholestasis in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease 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.

AIM: To evaluate the safety and efficacy of 3 doses of oral norUDCA (500mg/d, 1000mg/d or 1500 mg/d) compared with placebo in PSC in a RCT including 38centers from 12European countries.

METHODS: 161 PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for 12-weeks treatment followed by a 4-weeks follow-up. 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, 1000, and 1500 mg/d groups (p=0.029, =0.003, and <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 <1.5x ULN. Serious adverse events occurred in 7 in the 500mg/d-, 5 in the 1000mg/d-, 2 in the 1500 mg/d-group, and 3 in the placebo group, respectively. There was no difference in reported pruritus between treatment and placebo groups.

CONCLUSIONS: norUDCA significantly reduced ALP values dose dependently in all treatment arms. Safety profile of norUDCA was excellent and comparable to placebo. Consequently, a phase-3 trial of norUDCA in PSC appears justified. CLINICALTRIALS.

GOV NUMBER: NCT01755507 LAY SUMMARY: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed.In this phase II clinical study, a side chain shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA) significantly reduced serum alkaline phosphatase levels within 12 weeks as important surrogate marker in PSC in a dose-dependent manner. 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.