norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis

Area of Science:

• Hepatology
• Gastroenterology
• Clinical Pharmacology

Background:

• Primary sclerosing cholangitis (PSC) is a severe bile duct disease with limited treatment options.
• 24-norursodeoxycholic acid (norUDCA), a UDCA derivative, exhibits anti-cholestatic, anti-inflammatory, and anti-fibrotic properties in preclinical models.
• A European randomized controlled trial assessed norUDCA's safety and efficacy in PSC patients.

Purpose of the Study:

• To evaluate the safety and efficacy of three oral doses of norUDCA (500mg/d, 1,000mg/d, 1,500mg/d) compared to placebo in PSC patients.
• To determine the dose-dependent effect of norUDCA on serum alkaline phosphatase (ALP) levels.

Main Methods:

• A 12-week randomized controlled trial involving 161 PSC patients with elevated ALP levels.
• Patients were randomized to receive placebo or one of three norUDCA doses.
• The primary endpoint was the mean relative change in ALP levels from baseline to end of treatment.

Main Results:

• norUDCA demonstrated a dose-dependent reduction in ALP levels: -12.3% (500mg/d), -17.3% (1,000mg/d), and -26.0% (1,500mg/d) versus +1.2% for placebo (p<0.0001 for highest dose).
• Secondary endpoints, including other liver enzymes and normalization of ALP, also showed significant dose-dependent improvements.
• The safety profile of norUDCA was comparable to placebo, with no significant difference in reported pruritus.

Conclusions:

• norUDCA significantly reduces ALP levels in a dose-dependent manner in PSC patients.
• The drug exhibits an excellent safety profile, similar to placebo.
• These findings support the progression of norUDCA to phase III clinical trials for PSC treatment.