Cenicriviroc treatment improves liver fibrosis in people with NASH

Liz Highleyman
13 April 2018
Vlad Ratziu of Hôpital Pitié Salpêtrière, Paris. Photo by Liz Highleyman.

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 fibrosis.

Ratzui and 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).

Men and 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.

Participants 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.

After the 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.

At two 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.

Among study 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.

Among people 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.

People 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.

People 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.

Cenicriviroc 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.

Results 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."

A phase 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.


Ratziu V et al. Cenicriviroc treatment for adults with non-alcoholic steatohepatitis: year 2 analysis of the phase 2b CENTAUR study. The International Liver Congress, Paris, abstract GS-002, 2018. Journal of Hepatology 68:S1, 2018.