Cenicriviroc shows favorable pharmacokinetics for liver cirrhosis
In a phase 1 clinical trial, cenicriviroc showed favorable pharmacokinetics in patients with mild-to-moderate liver cirrhosis.
In the trial, Eric Lefebvre, MD, chief medical officer at Tobira Therapeutics, and colleagues assigned 15 patients with Child Pugh class A (n = 7) or class B cirrhosis (n = 8) to a regimen of 150 mg of cenicriviroc (CVC, Tobira) — an oral, potent immunomodulator that blocks the CCR2 and CCR5 receptors, which cause liver damage and often leads to cirrhosis, liver cancer or liver failure — once daily for 2 weeks and matched with 15 controls. Researchers established a treatment period of 14 days to allow enough time to reach “steady-state” and any changes in CVC pharmacokinetics in patients with hepatic impairment, according to the research.
Results showed CVC exposures were not increased in patients with mild cirrhosis compared with those in matched controls (AUC0-τ = 38%; Cmax was 40% lower). However, in patients with moderate cirrhosis, CVC exposures were increased compared with its matched controls (AUC0-τ = 55%; Cmax was 29% higher).
CCL2 and CCL4 increased rapidly after 1 and 2 weeks of treatment, suggesting potent CCR2 and CCR5 blockade (P < .05 for all compared with day 1), but was not associated with increases in hepatic inflammation or bacterial translocation biomarkers.
There were no notable differences in adverse events between patients and controls. Common adverse events observed were mild in nature and include headache and gastrointestinal disorders, and were found in at least two participants. Only one severe adverse event was reported in one person with a history of hepatitis C and cirrhosis, who experienced rapid increase in alanine aminotransferase and aspartate aminotransferase serums from day 1 to day 10 of treatment. However, this reduced after day 10 and the patient completed the study without dosing interruption.
“The results from this study are particularly relevant as we continue to explore the efficacy and safety of this dose of CVC in adults with [nonalcoholic steatohepatitis] and liver fibrosis in the ongoing CENTAUR study, where over one-third of subjects had severe fibrosis at entry and are therefore at risk of progression to cirrhosis,” Lefebvre said in a press release. “Prior to this study, there were limited studies evaluating whether cirrhosis impacts the metabolism and safety of CCR2 or CCR5 antagonists. These study findings show that CVC … can be dosed at 150 milligrams once daily in cirrhotic patients with mild-to-moderate hepatic impairment, and it was well tolerated.”
Researchers are currently investigating CVC in the phase 2b CENTAUR trial, which tests the safety and efficacy of CVC in 289 patients with NASH and liver fibrosis. Tobira expects to announce CENTAUR results in the third quarter of 2016, according to the release.
The FDA granted fast track designation to CVC as a potential therapy to treat adults with NASH and liver fibrosis in January 2015.
Disclosure: Lefebvre is employed by Tobira. Please see the study for all other researchers’ relevant financial disclosures.