NorUrsodeoxycholic acid helps rare bile duct disease with no current treatment

A phase 2 European trial showed that norUrsodeoxycholic acid leads to a significant reduction in serum alkaline phosphatase in people with primary sclerosing cholangitis, a rare but serious bile duct disease, according to a report presented at the International Liver Congress last month in Barcelona.

Primary sclerosing cholangitis (PSC) causes inflammation and eventual scarring of the bile ducts, leading to the build-up of bile acids in the liver. Early symptoms include fatigue and itching but over time it can lead to cirrhosis and liver or bile duct cancer; many people with PSC also have inflammatory bowel disease. The disease is most common among Northern Europeans, estimated at approximately 82,000 people in the European Union, or 6.3 cases per 100,000 persons. There are currently no good treatment options other than liver transplantation.

Prof Michael Trauner of the Medical University of Vienna and colleagues conducted a multinational randomised study to evaluate 24-norUrsodeoxycholic acid (norUDCA) as a treatment for PSC. NorUDCA is a homologue of ursodeoxycholic acid, an approved treatment for primary biliary cirrhosis. Trauner explained that despite only a small chemical change, norUDCA has very different effects from regular UDCA. It promotes detoxification of bile acids and has demonstrated anti-inflammatory and anti-fibrotic effects in mice.

This study – the first in PSC patients – included 159 participants from 38 centres in 12 European countries. At study entry they had elevated serum alkaline phosphatase (ALP), which occurs when bile ducts are blocked, a condition known as cholestasis.

Participants were randomly assigned to receive 500, 1000 or 1500mg/day of oral norUDCA or placebo for 12 weeks, with 4 weeks of post-treatment follow-up.

Patients taking all doses or norUDCA experienced significant reductions in ALP levels – the primary study endpoint – with the greatest declines seen in the highest dose group. ALP levels fell by 12.3% in the 500mg group, 17.3% in the 1000mg group and 26.0% in the 1500mg group, while rising by 1.2% in the placebo group; 13%, 42% and 31% of patients in the three dose groups, respectively, reached ALP levels below 1.5 times the upper limit of normal.

Treated participants also saw declines in alanine and aspartate aminotransferase (ALT and AST) liver enzymes and other liver disease biomarkers.

Treatment with norUDCA was generally safe and well tolerated, with about a third of people in all arms reporting adverse events. A total of 14 serious adverse events were reported, but they were not dose related and the highest number occurred in the lowest-dose group. Pruritus, or itching, was uncommon, mostly mild and occurred with similar frequency across the different dose and placebo arms.

Results from this study "show a significant reduction of [serum ALP] values within 12 weeks of treatment with norUDCA when compared to placebo," the researchers concluded. "The safety profile of all tested norUDCA doses was excellent and did not differ from the placebo group."

"Our study demonstrates that norUrsodeoxycholic acid could be a viable treatment option for patients with this chronic and debilitating condition," Prof Trauner said in an EASL press release. "NorUrsodeoxycholic acid provided a safe and effective option for patients with primary sclerosing cholangitis and the treatment warrants further investigation in a larger-scale phase 3 trial."

Prof Trauner reported that there was no significant change in quality of life observed in this study, but suggested it may take more than 16 weeks of treatment and follow-up for this to become apparent. While this phase 2 trial focused on biochemical improvement, phase 3 studies will look at longer-term clinical outcomes.

At a press conference discussing these findings, Prof Trauner said that while PSC is a rare disease, it is a major indication for liver transplants in parts of Northern Europe – and will likely become all the more so once hepatitis B is mostly prevented through vaccination and people are widely treated for hepatitis C.

Prof Heinrich Wedemeyer of Hannover Medical School in Germany described PSC as "the most awful liver disease" and said he was "extremely excited" that "for the first time there is some hope for these patients."