Gilead Presents Data on Multiple Investigational Regimens for the Treatment of Patients With Nonalcoholic Steatohepatitis (NASH) and Advanced Fibrosis

Gilead Sciences, Inc. (Nasdaq: GILD) today presented data from a proof-of-concept study of investigational combination therapies for patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH), combining the apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib with either the Acetyl-CoA carboxylase (ACC) inhibitor GS-0976 or the selective, non-steroidal Farnesoid X receptor (FXR) agonist GS-9674.

The proof-of-concept study (Oral #105) included 70 patients treated with either selonsertib 18 mg plus GS-0976 20 mg (n=20), selonsertib 18 mg plus GS-9674 30 mg (n=20), or each monotherapy (n=10 per group) once daily for 12 weeks. All patients in the study were diagnosed with NASH and liver fibrosis stages F2 to F3 based on biopsy, or by magnetic resonance elastography (MRE) and MRI proton density fat fraction (MRI-PDFF). The greatest changes observed after 12 weeks of treatment in the study were decreases in liver fat content (measured by MRI-PDFF), which occurred in regimens containing GS-0976. Improvements in liver biochemistry and/or markers of fibrosis were also observed across both combination arms of the study compared to baseline. In patients treated with selonsertib plus GS-0976, kinetic labeling revealed the largest reduction in the fractional synthesis rate of lumican, a marker of fibrogenesis. Similar rates of adverse events were observed between patients treated with single-agent and combination therapies. No patient discontinued treatment prematurely.

Based on these promising pre-clinical results and data from the proof-of-concept clinical study, Gilead has initiated a larger Phase 2b study of combination treatment with selonsertib, and/or GS-0976, and/or GS-9674 in patients with advanced fibrosis due to NASH.

Gilead is currently planning or conducting Phase 2 and 3 clinical trials evaluating single-agent and combination therapy approaches against multiple biologically relevant pathways associated with NASH – metabolic dysregulation, inflammation and fibrosis. Compounds in development include:

• Selonsertib (formerly GS-4997) – A small-molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), which promotes inflammation, apoptosis and fibrosis in settings of increased oxidative stress, which is characteristic of NASH and associated with its pathogenesis.
• GS-9674 – A selective, non-steroidal agonist of the Farnesoid X receptor (FXR), a nuclear hormone receptor that is highly expressed in the gastrointestinal tract and liver. FXR is the primary regulator of bile acid synthesis and plays important roles in glucose and lipid metabolism.
• GS-0976 – A small-molecule inhibitor of Acetyl-CoA carboxylase (ACC), an enzyme that is involved in de novo lipogenesis, which is the synthesis of lipids, including mediators of inflammation and fibrosis. ACC also upregulates the burning of fat in the liver through beta oxidation.