Details

Autor(en) / Beteiligte

• Fickert, Peter
• Hirschfield, Gideon M.
• Denk, Gerald
• Marschall, Hanns-Ulrich
• Altorjay, Istvan
• Färkkilä, Martti
• Schramm, Christoph
• Spengler, Ulrich
• Chapman, Roger
• Bergquist, Annika
• Schrumpf, Erik
• Nevens, Frederik
• Trivedi, Palak
• Reiter, Florian P.
• Tornai, Istvan
• Halilbasic, Emina
• Greinwald, Roland
• Pröls, Markus
• Manns, Michael P.
• Trauner, Michael

Titel

norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis

Ist Teil von

• Journal of hepatology, 2017-09, Vol.67 (3), p.549-558

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• [Display omitted] •There is an urgent need for novel drugs for PSC.•In this phase II clinical trial, norUDCA reduced serum ALP levels within 12weeks.•norUDCA’s effects on liver enzymes were dose-dependent.•The safety profile of norUDCA was excellent. 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 (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC. 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. 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. 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.