Obeticholic acid (Ocaliva)
led to a significant improvement in liver fibrosis related to non-alcoholic
steatohepatitis (NASH), offering a potential future option for an increasingly
common liver disease with no good current therapies, researchers reported
yesterday at The International Liver Congress in Vienna.
Younossi of Inova Fairfax Medical Campus in Falls Church, Virginia, who
presented the findings at a press conference and at the meeting's opening
session, said that the study results represent a "watershed moment"
for the field, as this is the first large randomised clinical trial to show a
benefit for a NASH therapy.
Non-alcoholic fatty liver disease (NAFLD) and its more severe form,
NASH, are responsible for a growing
proportion of advanced liver disease. The build-up of fat in the liver
triggers inflammation, which over time can lead to the development of scar
tissue (fibrosis), cirrhosis (severe scarring) and liver cancer. Fatty liver
disease is associated with obesity and the metabolic syndrome – a growing problem
worldwide. Lacking effective treatment, current management relies on lifestyle
changes such as weight loss and exercise.
is an urgent need for effective treatment regimens for NASH, a common liver
disease which can lead to cirrhosis, liver failure and need for transplant," Younossi
said in a press
release issued by the European Association for the Study of the
Liver (EASL). "These first results from the REGENERATE study give us hope
that a new targeted approach to NASH treatment may soon become available and
potentially reverse some of the liver damage associated with this important
Younossi and colleagues
conducted a phase 3 study to evaluate obeticholic acid, or OCA, as a treatment for
NASH. The study's primary endpoints were
improvement of fibrosis by at least one stage with no worsening of NASH, or
NASH resolution with no worsening of fibrosis.
Intercept Pharmaceuticals, is a farnesoid X
receptor (FXR) agonist that activates receptors which play a role in lipid
metabolism and liver regeneration after injury. Preclinical studies showed that
FXR activation protects against damage from liver fat build-up, lowers blood
lipid levels and improves insulin sensitivity; a previous phase 2 study showed
improvement in liver fibrosis and histology. OCA is being developed as a
treatment for both NASH and primary biliary cholangitis, a bile duct disease.
The REGENERATE trial enrolled people with moderate to
advanced fibrosis due to NASH; 44% had stage F2 and 56% had stage F3 fibrosis. About
60% were women, around 90% were white and the average age was 55 years. People
with other chronic liver diseases, including hepatitis B or C, and those with
'significant' alcohol consumption were excluded. More than half had diabetes
and were taking statins or other lipid-lowering medications.
Participants were randomly assigned to receive 10mg or
25mg OCA or a placebo once daily. Liver biopsies were done at baseline and 18
months after starting treatment. A total of 931 people were included in the
In an 18-month interim intent-to-treat analysis, 23.1%
of participants in the 25mg OCA arm and 17.6% in the 10mg arm experienced fibrosis improvement without worsening of
NASH, compared with 11.9% in the placebo group, Younossi reported. The differences between both OCA
arms and the placebo arm were statistically significant.
received 25mg OCA were also more likely to show improvement in hepatocellular ballooning (35.1% versus 23.2% in the placebo arm) and
lobular inflammation (44.2% versus 35.7%, respectively). ALT, AST and GGT liver
enzyme levels – an indicator of inflammation – decreased in dose-dependent manner,
and more than half achieved ALT and AST normalisation.
In a per protocol analysis of 668 people who completed at least 15
months of treatment and had post-treatment biopsies, 38.0% of those in the 25mg
OCA arm experienced at least a one-stage improvement in fibrosis and 13.3% had
at least a two-stage improvement, while 13.1% had worsening fibrosis. In the
placebo group, about equal proportions improved and worsened.
second primary endpoint, improvement in NASH without worsening fibrosis, did
not reach the threshold for significance in the intent-to-treat population:
11.7% and 11.2%, respectively, in the 25mg and 10mg OCA arms versus 8.0% in the
placebo arm. However, in a pre-specified analysis that also included an
exploratory group of people with mild (stage F1) fibrosis, those who received
25mg OCA were significantly more likely to experience NASH resolution (14.9%
versus 7.9% in the placebo arm).
OCA was generally
safe and well tolerated. Severe adverse events occurred in 14% of people in the
OCA 25mg arm and 11% in the other two arms. The most common side-effect was
pruritus, or itching, reported by 51% in the OCA 25mg arm, 28% in the 10mg arm
and 19% in the placebo arm. This was usually mild to moderate, but 9% in the
high-dose OCA group stopped treatment due to pruritus. LDL cholesterol rose by
week 4, but fell back toward the baseline level by the end of follow-up.
Follow-up is ongoing to evaluate longer-term clinical outcomes.
"Treatment with OCA 25mg improved
liver fibrosis, key histologic features of steatohepatitis and liver
biochemistry, demonstrating consistent efficacy with an overall adverse event profile
similar to previous studies," the researchers concluded.
Commenting on the study, EASL vice-secretary Prof Philip Newsome said,
"These data are very exciting as they demonstrate for the first time in a
phase 3 trial that medical therapy, in this case obeticholic acid, is able to
improve liver fibrosis compared to placebo—a key treatment goal in NASH."