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Obeticholic acid improves liver fibrosis in people with NASH

Liz Highleyman
12 April 2019
Image from the EASL livestream of Zobair Younossi presenting at The International Liver Congress.

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.

Dr Zobair 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.

"There 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 liver disease."

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.

OCA, from 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 intent-to-treat population.

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.

Those who 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.

The 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."


Younossi Z et al. Results from REGENERATE: a phase 3 international, randomized, placebo-controlled study evaluating obeticholic acid treatment for NASH
. The International Liver Congress, Vienna, abstract GS-07, 2019. Journal of Hepatology 70:e5, 2019

Watch this presentation on the conference website.