1Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. firstname.lastname@example.org.
GS-9620 is a potent oral agonist of toll-like receptor 7, a key modulator of the innate immune response. In healthy volunteers, low doses of GS-9620 (2, 4, and 6 mg) induced significant expression of peripheral interferon-stimulated-gene (ISG) mRNA in the absence of detectable serum interferon-alpha and systemic adverse events (AEs). We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in treatment-naïve patients chronically infected with hepatitis C virus (HCV) genotype 1.
In this double-blind, placebo-controlled study, 51 patients were randomised 5:1 (active: placebo) to receive either a single dose or two once-weekly doses of GS-9620 at four dose levels (0.3, 1, 2, and 4 mg) or placebo. Pharmacodynamic assessments included peripheral ISG15 mRNA expression, serum interferon-alpha and interferon-γ-inducible protein (IP)-10 levels, and HCV RNA quantification.
GS-9620 was well tolerated at all doses. Most AEs were mild or moderate in severity. GS-9620 exhibited dose-linear pharmacokinetics with a median half-life in plasma of 18 hours. Transient, dose-dependent ISG15 induction was observed at 1, 2, and 4 mg, with peak mean fold-change within 48 hours followed by a decline to baseline levels within 7 days of dosing. Serum IFN-alpha induction post baseline was detected in 16.7% (8/48) of patients. No clinically significant reductions in HCV RNA were observed.
GS-9620 was safe, well-tolerated, and biologically active in patients with HCV infection. Induction of ISG15 occurred in the absence of detectable serum interferon-alpha or systemic AEs in most patients, supporting a pre-systemic mechanism of action.