Neil Osterweil

November 18, 2016

BOSTON — Cenicriviroc (Tobira Therapeutics), an investigational once-daily oral therapy, can improve fibrosis in patients with nonalcoholic steatohepatitis (NASH), according to preliminary results from the phase 2b CENTAUR trial.

Patients who received the drug were twice as likely as those who received placebo to experience an improvement in fibrosis of at least one stage without a worsening of steatohepatitis, said Arun Sanyal, MD, from Virginia Commonwealth University in Richmond.

The "treatment benefits were greater in subjects with greater disease activity and stage," he reported here at The Liver Meeting 2016. However, during the first year of the ongoing trial, the drug did not meet its primary efficacy end point.

It is estimated that 6 million to 10 million people in the United States with high-risk NASH have experienced fibrotic remodeling of the liver and are at particularly high risk for progression to cirrhosis, hepatocellular carcinoma, or death from liver failure.

Cenicriviroc is a C–C chemokine receptor type 2 and type 5 antagonist with a half life in plasma of 30 to 40 hours. It was designed to interrupt the inflammatory cascade in NASH that leads to fibrogenesis, Dr Sanyal explained.

In animal models, the drug has been shown to have anti-inflammatory and antifibrotic activity. In the human trials conducted to date, with more than 800 patients, it has been shown to be well tolerated in patients with cirrhosis and mild to moderate hepatic impairment, he reported.

CENTAUR at 1 Year

The CENTAUR trial involved 289 patients with histologically defined NASH; an NAFLD Activity Score of at least 4; liver fibrosis stage of 1 to 3, determined using NASH Clinical Research Network criteria; and diabetes or the metabolic syndrome (NCT02217475).

Table. Baseline Characteristics of the Study Cohort

Characteristic Percent (n = 289)
Stage of liver fibrosis  
 1 33
 2 29
 3 38
NAFLD Activity Score  
 4 26
 5 30
 6 30
 7 12
 8 2

 

Study participants were randomized to one of three groups in a 2:1:1 ratio: cenicriviroc 150 mg daily for 2 years; placebo for the first year and cenicriviroc for the second year; and placebo for 2 years.

In an intention-to-treat analysis at 1 year, the primary efficacy end point — improvement in NAFLD Activity Score by at least 2 points, a reduction of at least 1 point in lobular inflammation or hepatocellular ballooning, and no concurrent worsening of fibrosis stage — was met by 19% of patients in the cenicriviroc group and 16% of those in the placebo group (P = .0519).

The secondary end point of complete resolution of NASH and no worsening of fibrosis was met by 8% of patients in the cenicriviroc group and 6% of those in the placebo group, but this difference was not significant.

However, there was a significant difference between the cenicriviroc and placebo groups in the secondary end point of improvement in fibrosis stage with no worsening of NASH (20% vs 10%; P = .023).

For the end point of improvement in fibrosis with no worsening of NASH for all stages of fibrosis, cenicriviroc was numerically but not statistically better than placebo. However, cenicriviroc was significantly better when patients with stage 2 and stage 3 fibrosis were combined (P = .049).

In an analysis of four markers of systemic inflammation — interleukin(IL)1-beta, IL-6, high-sensitivity C-reactive protein, and fibrinogen — the drug demonstrated more anti-inflammatory activity than placebo.

The incidence of treatment-emergent adverse events and drug-related events was similar in the two groups. There were more serious adverse events in the cenicriviroc group than in the placebo group (16 vs 10), but only one patient in the cenicriviroc group and two patients in the placebo group discontinued because of an adverse event.

 
It's exciting that we have a medication that improves fibrosis. That's the ultimate end point.
 

"It's exciting that we have a medication that improves fibrosis. That's the ultimate end point that we want," said session comoderator Cynthia Levy, MD, from the University of Miami, who was not involved in the study.

"These are only the first year of the data, however, so we have to wait for the second year and the remaining data that are going to come out," she told Medscape Medical News. "We did not see an improvement in steatohepatitis yet, and I'm curious why not, but I'm impressed with the improvement in fibrosis."

This study was supported by Tobira Therapeutics. Dr Sanyal reports financial relationships with numerous pharmaceutical companies, and has received research funding from Tobira Therapeutics. Dr Levy reports financial relationships with numerous pharmaceutical companies, including Tobira Therapeutics, and has participated in speaking and teaching activities for Medscape.

The Liver Meeting 2016: American Association for the Study of Liver Diseases (AASLD): Abstract LB-1. Presented November 14, 2016.

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