Other Infections

Ezetimibe Did Not Reduce Liver Fat in NASH Trial, New Therapies Under Study

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Ezetimibe (Zetia) did not perform significantly better than placebo in reducing liver fat among people with non-alcoholic steatohepatitis (NASH), according to a report in the December 6 edition of Hepatology. In related news, the FDA has designated Tobira's cenicriviroc -- also active against HIV -- as a fast-track therapy for NASH and Gilead Sciences announced a partnership to enter the NASH arena.

Non-alcoholic steatohepatitis is characterized by fat buildup in the liver along with liver inflammation and fibrosis. NASH and non-alcoholic fatty liver disease (NAFLD) -- fatty liver without inflammation and liver damage -- are becoming more common, likely due to the rising prevalence of obesity. Some people with hepatitis B or C (especially HCV genotype 3) also have fatty liver disease, compounding the potential for advanced liver damage.

Rohit Loomba from the University of California at San Diego and fellow investigators with the MOZART trial tested Ezetimibe as a potential treatment for NASH. Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density-lipoprotein (LDL), and uncontrolled studies suggested it could reduce liver fat, the study authors noted as background.

This double-blind trial included 50 participants with biopsy-proven NASH. They were randomly assigned to receive either 10 mg ezetimibe or placebo daily for 24 weeks. The primary outcome was change in liver fat as measured by magnetic-resonance imaging-derived proton-density-fat-fraction (MRI-PDFF) in 9 liver segments, as well as histological response and elastography liver stiffness measurement.

Results

"In this randomized, double blind, placebo-controlled MOZART trial, ezetimibe was not better than placebo in reducing liver fat or improving liver histology in NASH," the authors concluded, though the study did demonstrate that combining MRI-PDFF and elastography can be useful for non-invasively assessing treatment response in NASH studies.

Cenicriviroc for NASH

Tobira Therapeutics announced this month that the U.S. Food and Drug Administration has granted fast-track status for its dual CCR5/CCR2 inhibitor cenicriviroc for the treatment of NASH in people with liver fibrosis.

Cenicriviroc blocks both the CCR5 co-receptor that most strains of HIV use to enter cells, as well as the CCR2 receptor that plays a role in inflammatory response. The drug has shown good antiviral activity and tolerability as a treatment for HIV. Studies presented at the 2013 AASLD Liver Meeting showed that cenicriviroc had anti-inflammatory and anti-fibrotic activity in mice and rats with induced liver damage.

Tobira is currently enrolling participants in the Phase 2 CENTAUR trial (NCT02217475), a randomized, double-blind study comparing cenicriviroc versus placebo in approximately 250 patients with NASH and liver fibrosis.

"We believe this fast track designation is further recognition of both the critical need for effective therapies for patients with NASH and liver fibrosis and of cenicriviroc’s potential to treat this serious condition," Tobira CEO Laurent Fischer stated in a company press release.

Gilead Acquires NASH Candidates

Gilead Sciences announced this month that it has acquired the German company Phenex Pharmaceuticals' development program for NASH and other liver diseases.

According to a company press release, the agreement gives Gilead access to Phenex's portfolio of small molecule farnesoid X receptor (FXR) agonists for the treatment of liver disease. FXR is a nuclear hormone receptor that regulates bile acid and lipid and glucose homeostasis, which can help reduce liver steatosis and inflammation and may help prevent fibrosis, according to the release.

One of these Phenex candidates, Px-104, is now in Phase 2 trials. Another FXR agonist, Intercept Pharmaceuticals' obeticholic acid, has shown promising efficacy in people with NASH and patients with primary biliary cirrhosis

1/29/15

Reference

R Loomba, CB Sirlin, B Ang, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: Assessment by novel MRI and MRE in a randomized trial (MOZART Trial). Hepatology. December 6, 2014 (Epub ahead of print).

Other Sources

Tobira Therapeutics. Tobira Therapeutics’ Cenicriviroc Granted Fast Track Designation by the FDA for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Patients with Liver Fibrosis. Press release. January 6, 2015.

Gilead Sciences. Gilead Sciences Announces Acquisition of Phenex Pharmaceuticals’ Development Program for Non-Alcoholic Steatohepatitis (NASH) and Other Liver Diseases. Press release. January 6, 2015.