Major Finding: From a mean baseline ALT of 106 IU/L, levels dropped by 43% following 4 weeks of the investigational drug GS-9450 at 40 mg/day and by 30% with 10 mg/day, compared with 2% with placebo.
Data Source: A phase II dose-ranging study involved 124 patients with biopsy-confirmed NASH treated at 6 French and 35 U.S. centers.
Disclosures: The study was sponsored by Gilead Sciences. Dr. Ratziu is a consultant to the company.
VIENNA — A novel antiapoptotic drug has reduced markers of liver damage in patients with nonalcoholic steatohepatitis in a phase II trial.
Four weeks of therapy at the highest studied dose of the once-daily hepatoselective oral agent GS-9450 resulted in normalization of serum alanine aminotransferase levels in 35% of patients with NASH, compared with 9% in the placebo arm of the double-blind randomized multicenter trial, said Dr. Vlad Ratziu.
Based on the favorable safety and efficacy demonstrated in this study, the next step for GS-9450 will be a larger clinical trial with histologic end points, added Dr. Ratziu of Pierre and Marie Curie University, Paris.
GS-9450 is a potent inhibitor of caspases 1, 8, and 9. These enzymes modulate apoptosis, identified as one of the major mechanisms of liver injury in NASH. The drug has a liver-to-blood-concentration ratio of 100:1. GS-9450 also is being developed for a separate indication in the treatment of liver injury in patients with chronic hepatitis C.
The phase II dose-ranging study involved 124 patients with biopsy-confirmed NASH treated at 6 French and 35 U.S. centers. They were randomized to 4 weeks of GS-9450 at 1, 5, 10, or 40 mg or placebo once daily. From a mean baseline alanine aminotransferase (ALT) of 106 IU/L, levels of the liver enzyme dropped by 43% following 4 weeks of GS-9450 at 40 mg/day and by 30% with 10 mg/day, vs. 2% with placebo. Levels of serum aspartate aminotransferase followed suit.
Serum levels of CK-18 caspase cleavage fragments, thought to be a marker of apoptotic liver disease, declined in the 10- and 40-mg treatment arms. No severe adverse events occurred. Mild to moderate nausea, fatigue, and arthalgia were more common in GS-9450-treated patients than with placebo.
One audience member voiced concern that an apoptosis-blocking agent could have a carcinogenic effect.
Dr. Ratziu replied that animal studies actually suggest GS-9450 has the opposite effect, but more clinical data are needed to provide definitive reassurance.
“One possible explanation for the decrease in neoplastic risk seen in animal models is that this is a selective caspase inhibitor, not a pan-caspase irreversible inhibitor,” the gastroenterologist added.
Dr. Peter Ferenci called this GS-9450 study one of the meeting highlights. GS-9450 represents a novel therapeutic approach in NASH, an important disease for which there is a clear unmet need for better treatments. There are no drugs of established efficacy.
“Treatment today centers on weight loss and recommendations for increased mobility, which are very hard for many patients to follow,” said Dr. Ferenci, professor of medicine at the Medical University of Vienna.
NASH is an advanced form of nonalcoholic fatty liver disease (NAFLD). It's estimated that up to 5% of Americans have NASH, which often leads to cirrhosis. Up to 20% of Americans have NAFLD.
The prevalences of both NASH and NAFLD are rising in parallel with the obesity epidemic. Both conditions are increasingly being diagnosed in heavy children.
Elsewhere at the meeting, Dr. Ulrich Leuschner reported that high-dose ursodeoxycholic acid proved no more effective than placebo for the treatment of NASH in a randomized trial. This finding is a disappointment in light of several earlier open-label studies suggesting a beneficial effect, noted Dr. Leuschner of J.W. Goethe University, Frankfurt, Germany.
He reported on 186 patients with histologically confirmed NASH who were randomized to 23–28 mg/kg per day of ursodeoxycholic acid or placebo for 18 months. Posttreatment liver biopsies were obtained in 135 patients. They showed no significant differences in rates of improved liver histology between the ursodeoxycholic and placebo groups; nor were there any overall significant differences in liver function tests.
The study's only hope was the finding of significant improvements in intra-acinar inflammation and gamma glutamyltransferase in a relatively small but specific patient subgroup of younger mildly overweight men.
Dr. Ratziu is a consultant to Gilead Sciences, which sponsored his study. Dr. Leuschner is a consultant to Dr. Falk Pharma GmbH, which supported the ursodeoxycholic acid trial.