- Oral ACC Inhibitor Led to Significant Reductions in Measures of Liver Fat and Fibrosis -
- Results from the GS-0976 Phase 2 Study and 18 Other Abstracts from Across Gilead’s Liver Fibrosis Pipeline Presented at The Liver Meeting® 2017
“In patients with advanced fibrosis, NASH may lead to severe complications including end-stage liver disease, hepatocellular carcinoma and the requirement for liver transplantation,” said ACC plays a role in one of several biologically relevant pathways associated with disease progression in NASH. ACC catalyzes the first step in hepatic de novo lipogenesis, the synthesis of fatty acids that contribute to hepatic steatosis and, subsequently, inflammation and liver fibrosis. The study included 126 patients who were randomized to receive GS-0976 20 mg (n=49), GS-0976 5 mg (n=51), or placebo (n=26) once daily for 12 weeks. All patients in the study were diagnosed with NASH and liver fibrosis stages F1 through F3 based on biopsy, or by magnetic resonance elastography (MRE) and MRI proton density fat fraction (MRI-PDFF). Patients receiving GS-0976 20 mg demonstrated significant decreases in liver fat content (measured by MRI-PDFF) compared to placebo after 12 weeks of treatment. Patients treated with GS-0976 20 mg also experienced a significant decrease in TIMP-1, a serum marker associated with liver fibrosis. Differences between GS-0976 5 mg and placebo were not statistically significant. Data for these efficacy endpoints are summarized in the table below. Relative (%) Changes in Imaging, ALT and Serum Fibrosis Markers at Week 12*
In other measures, including liver stiffness by FibroScan, liver stiffness by MRE, serum ALT and PIII-NP, a serum marker of fibrogenesis, no statistically significant differences were observed between the treatment and placebo arms of the study. At week 12, a median relative change in triglycerides (TG) from baseline of +11 percent, +13 percent and -4 percent was observed in patients receiving GS-0976 20 mg, GS-0976 5 mg and placebo, respectively. Asymptomatic Grade 3 or 4 TG elevations (>500 mg/dL) were observed in 16 patients receiving GS-0976 20 mg (n=7) or 5 mg (n=9); the primary factor associated with such elevations was a baseline TG level >250 mg/dL (p<0.001). The majority of patients with such elevations either responded to fibrate or fish oil therapy (n=4) or resolved without additional treatment or cessation of GS-0976 (n=7). GS-0976 was well-tolerated. Nausea, abdominal pain and diarrhea were the most common adverse events. Other Gilead studies being presented at The Liver Meeting include preclinical data examining the combination of inhibitors of ACC and apoptosis signal-regulating kinase 1 (ASK1) in rodent models of NASH. These data suggest that the combination of agents resulted in greater anti-fibrotic and anti-steatotic efficacy than either agent alone (Abstract #425; named a Presidential Poster of Distinction). Gilead is currently conducting clinical studies evaluating combinations of the ASK1 inhibitor selonsertib, ACC inhibitor GS-0976 and the selective, non-steroidal Farnesoid X receptor (FXR) agonist GS-9674 in patients with NASH. Additional abstracts describe the accuracy of noninvasive markers to predict improvements in liver histology in response to treatment in a Phase 2 study of selonsertib, including reductions in fibrosis with MRE (Abstract #2104) and liver fat with MRI-PDFF (Abstract #2169). Phase 3 studies are ongoing with selonsertib in patients with advanced fibrosis due to NASH. Gilead is also presenting multiple abstracts regarding primary sclerosing cholangitis (PSC), a progressive cholestatic liver disease with no approved therapies. These include presentations on the role of magnetic resonance cholangiopancreatography (MRCP) in PSC including a Presidential Plenary Oral Presentation (Abstract #140) describing a novel MRCP-based risk score for predicting PSC-related complications; an innovative technique for quantifying biliary tree volume in PSC (Abstract #292); prospective data describing the natural history of radiologic progression in PSC (Abstract #279; a Presidential Poster of Distinction); and the development and validation of a PSC-specific patient reported outcome (PRO) measure (Abstract #1351; a Presidential Poster of Distinction). These studies will enhance our understanding of PSC and aid in the development of novel therapies. Gilead is currently conducting a Phase 2 study of the FXR agonist GS-9674 in patients with PSC. http://investors.gilead.com/phoenix.zhtml?c=69964&p=irol-newsArticle&ID=2310692 Navigate This Blog
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Tuesday, October 24, 2017
The Liver Meeting® 2017 - Gilead Phase 2 Results for GS-0976 in Nonalcoholic Steatohepatitis (NASH)
Gilead Announces Phase 2 Results for GS-0976 in Nonalcoholic Steatohepatitis (NASH)
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