Cenicriviroc, a drug that
blocks both CCR5 and CCR2 receptors on immune cells, continued to show an
anti-fibrotic effect in people with non-alcoholic steatohepatitis (NASH) after two
years of follow-up, according to a study presented yesterday at the 2018 International Liver
Congress in Paris.
Twice as many people treated with cenicriviroc maintained
at least a one-stage improvement in fibrosis compared to those who received a
placebo, with the greatest benefit seen in people with the most severe liver
damage, Vlad Ratziu of Hôpital Pitié Salpêtrière reported.
Non-alcoholic fatty liver disease (NAFLD) and NASH, its more severe
form, account for a growing proportion of liver disease worldwide. Often
associated with obesity and the metabolic syndrome, the build-up of fat in the
liver triggers inflammation and development of scar tissue (fibrosis), which
can interfere with normal liver function. Over time, it can lead to cirrhosis,
liver cancer and the need for a liver transplant. To date there are no good
treatments for NAFLD and lifestyle changes such as weight loss are the mainstay
of its management.
Abnormal fat deposits in the liver.
Cenicriviroc blocks CCR5,
one of the co-receptors HIV uses to enter T-cells, and it was previously studied as an HIV treatment. It also interferes with CCR2, a cytokine that promotes
migration of monocytes and activation of collagen-producing stellate cells, and
it has been found to have anti-inflammatory and anti-fibrotic activity. Researchers previously reported that HIV-positive people who received cenicriviroc
for two years in an HIV treatment study saw a decrease in biomarkers of liver
colleagues conducted the CENTAUR study to evaluate cenicriviroc for the treatment of people with NASH accompanied
by liver fibrosis. This randomised phase IIb study enrolled 298 participants in
Europe, the US, Australia and Hong Kong who had NASH (NAFLD activity score of 4
or higher) and mild to severe fibrosis (stages 1-3).
women were equally represented, most were white and the mean age was 54 years. A
third had mild fibrosis and 38% had advanced liver fibrosis at baseline. Most
were overweight and half had type 2 diabetes.
were initially randomly assigned to receive 150mg once-daily oral cenicriviroc
or a placebo for one year. They received liver biopsies at baseline and at the
end of the first year of treatment. The primary outcome was improvement in steatosis
(NAFLD activity score) without worsening of fibrosis.
As reported last year in the journal Hepatology, there was no significant difference in the proportion
of people in the cenicriviroc and placebo groups with least a 1-point NAFLD
score improvement (16% and 19%, respectively). However, twice as many people receiving
cenicriviroc saw at least a 1-stage improvement in fibrosis with no worsening
of steatosis (20% vs 10%, a statistically significant difference). People
taking cenicriviroc also had larger decreases in inflammation biomarkers. Improvement
was greatest in people who started out with the worst inflammatory activity and
fibrosis at baseline.
one-year analysis, participants were re-allocated. Those initially assigned to
cenicriviroc continued to take it, while those initially assigned to the
placebo group were re-randomised, with half switching to cenicriviroc and half
staying on the placebo. After the second year on treatment they underwent a
third liver biopsy. The 242 people in the two-year analysis had characteristics
similar to those in the earlier analysis.
years, 26% of people in the original cenicriviroc group and 22% in the original
placebo group had at least a 1-stage improvement in fibrosis; 15% and 17%,
respectively, had fibrosis improvement and no worsening of steatosis. Neither
difference was statistically significant. Substantially more people with
moderate or advanced fibrosis saw at least a 2-stage improvement in the
cenicriviroc arm without worsening of steatosis – 11% vs 3% at two
years – though this also did not reach statistical significance.
participants who did not see an improvement at Year 1 in the original placebo
group, 24% of those who switched to cenicriviroc saw at least a 1-stage
fibrosis improvement without worsening of steatosis, compared with 17% of those
who stayed on the placebo.
who showed improvement at Year 1, cenicriviroc was associated with significantly
greater maintenance of antifibrotic response, Ratziu reported: 60% of people in
the original cenicriviroc arm maintained at least a 1-stage improvement in
fibrosis, compared with 30% of those in the original placebo group.
who started with advanced fibrosis were mostly likely to see sustained
improvement. Among those with stage 3 fibrosis at baseline, 86% taking
cenicriviroc and 60% taking the placebo maintained at least a 1-stage improvement
at Year 2. In addition, 40% of those with moderate fibrosis and 33% with mild
fibrosis maintained improvement on cenicriviroc, while no one with stage 2 or 1
fibrosis had sustained improvement on the placebo. However, the numbers in
these subgroups were small and the differences could have been due to chance.
taking cenicriviroc continued to have more marked decreases in biomarkers of
systemic inflammation at year two, including interleukin-1-beta,
interleukin 8, high-sensitivity C-reactive protein and fibrinogen.
remained generally safe and well tolerated at two years, with no new or
unexpected side-effects, Ratziu reported. About 15% in both the original
cenicriviroc and placebo groups experienced severe or life-threatening adverse
events. No one in either group had drug-related serious adverse events and
there were no deaths.
from this Year 2 exploratory analysis "corroborate cenicriviroc's
antifibrotic activity in adults with NASH and liver fibrosis," the study
investigators concluded. "Twice as many cenicriviroc-treated patients
achieving >1-stage improvement in fibrosis at Year 1 maintained this
benefit at Year 2 compared to placebo, especially in stage 3 fibrosis."
III study of cenicriviroc for the treatment
of liver fibrosis in people with NASH, known as AURORA, is currently underway. Cenicriviroc
is also being studied in combination with a farnesoid X receptor (FXR) agonist for fatty liver disease.