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
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.
- alkaline phosphatase (ALP)
ALP is an enzyme in the liver, bile ducts and bone. When the bile ducts in the liver are obstructed, ALP is released into the bloodstream, resulting in elevated enzymes in blood tests.
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
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
Treated participants also saw declines in alanine and
aspartate aminotransferase (ALT and AST) liver enzymes and other liver disease
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
"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
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."