Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

Abstract

GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 (TLR8) in clinical development for the treatment of chronic hepatitis B (CHB). In this study, we evaluated the antiviral efficacy of GS-9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus (HBV). WHV-infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS-9688 or 3 mg/kg GS-9688. Vehicle and 1 mg/kg GS-9688 had no antiviral effect, whereas 3 mg/kg GS-9688 induced a >5 log 10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS-9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti-WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS-9688 was confirmed in a second woodchuck study. The antiviral response to GS-9688 did not correlate with systemic GS-9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells (PBMC) to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells (T FH) and various other immune cell subsets may play a role in the antiviral response to GS-9688. Conclusion: Finite, short-duration treatment with a clinically relevant dose of GS-9688 is well tolerated and can induce a sustained antiviral response in WHV-infected woodchucks. The identification of a baseline intrahepatic transcriptional signature associated with response to GS-9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect. Approximately 260 million individuals are chronically infected with hepatitis B virus (HBV), and over half a million people are estimated to die each year due to liver diseases associated with chronic hepatitis B (CHB), such as cirrhosis and hepatocellular carcinoma (HCC). Immunological control of CHB ("functional cure") is defined as sustained loss of HBV surface antigen (HBsAg) off treatment, with or without seroconversion to anti-HBs antibody. Several nucleos(t)ide analogs, as well as interferon-alpha (IFN-α), are approved for the treatment of CHB. These therapies reduce viremia and

Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B

“…Furthermore, woodchucks are fully immunocompetent and the animal model is supported by the recent identification of the liver transcriptome and genome [36,37]. Thus, woodchucks are increasingly utilized for the evaluation of new antiviral drugs for treatment of CHB and HCC [28,31,33,[38][39][40][41][42][43][44][45], and their preclinical use is predictive of therapeutic efficacy of NAs [40,46] and immunomodulators [15,47,48] against HBV in patients.…”

Characterization of Seasonal Pharmacokinetic Variability in Woodchucks

“…The eastern woodchuck is a hibernating species that is being extensively used in laboratory to study the antiviral efficacy for treatment of chronic HBV infection (Rajagopalan et al, 1996;Genovesi et al, 1998;Mason et al, 1998;Dandri et al, 2000;Korba et al, 2000;Bryant et al, 2001;Menne et al, 2005), functional cure of HBV (Menne et al, 2015;Paulsen et al, 2015;Daffis et al, 2017;Daffis et al, 2020) and treatment of WHV associated HCC (Tennant et al, 2004;Iyer et al, 2019).…”

“…DMD Fast Forward. Published on September 5, 2020 as DOI: 10.1124/dmd.120.000140 at ASPET Journals on November 3, 2020 dmd.aspetjournals.org Downloaded from 7 9688) (Menne et al, 2015;Paulsen et al, 2015;Daffis et al, 2017;Daffis et al, 2020;Mackman et al, 2020).…”

Recent Advances in Understanding, Diagnosing, and Treating Hepatitis B Virus Infection

“…Selgantolimod (GS-9688) is an orally active, potent, and selective toll-like receptor 8 (TLR8) agonist in clinical development for the treatment of chronic hepatitis B. It was shown to induce a sustained antiviral response in the woodchuck model of CHB [ 173 , 174 ], and was well-tolerated in CHB patients in a randomized blind placebo-controlled study [ 109 ]. Currently, GS-9688 is undergoing phase II clinical trials.…”