Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B

Abstract

Background & Aims New therapies for chronic hepatitis B (CHB) are urgently needed since current treatments rarely lead to cure. We evaluated whether the oral small molecule toll-like receptor (TLR7) agonist GS-9620 could induce durable anti-viral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to human hepatitis B virus (HBV). Methods After evaluating the pharmacokinetics, pharmacodynamics and tolerability of oral GS-9620 in uninfected woodchucks, adult woodchucks chronically infected with WHV (n=7 per group) were dosed with GS-9620 or placebo for 4 or 8 weeks with different treatment schedules. Results GS-9620 treatment induced rapid, marked and sustained reduction in serum viral DNA (mean maximal 6.2 log10 reduction), and hepatic WHV DNA replicative intermediates, WHV cccDNA and WHV RNA, as well as loss of detectable serum WHV surface antigen (WHsAg). GS-9620 treatment also induced a sustained antibody response against WHsAg in a subset of animals. Strikingly, treatment reduced the incidence of hepatocellular carcinoma (HCC) from 71% in the placebo group to 8% in GS-9620-treated woodchucks with sustained viral load reduction. GS-9620 treatment was associated with reversible increases in serum liver enzymes and thrombocytopenia, and induced intrahepatic CD8+ T cell, NK cell, B cell and interferon (IFN) response transcriptional signatures. Conclusions The data demonstrate that short duration, finite treatment with the oral TLR7 agonist GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB, and support investigation of this compound as a therapeutic approach to attain a functional cure in CHB patients.

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

“…Recently, oral TLR7 ligands successfully induced viral control in Woodchuck and chimpanzee HBV-animal models (Menne et al, 2015;Lanford et al, 2013). Disappointingly in humans, oral TLR7 ligands thus far have not achieved any beneficial effect, despite that treatment was well tolerated (Gane et al, 2015;Janssen et al, 2017).…”

Hepatitis B: Working Towards a Cure

“…Viral load suppression of 2.2 logs initially was found to be sustained by a minimum of 1 log for 2-4 months after initial dosing. In the woodchuck model, there was a similar multi-log reduction in viral load, as well as WHsAg loss, WHsAb seroconversion, and reduced cccDNA levels and HCC incidence, sustained over the 35-week trial period [37].…”

Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies

“…As expected, GS-9620 administration induced the production of IFNchemokines, upregulated ISGs expression in the liver, and activated NK cells and other lymphocyte subsets. Importantly, similar effects were also observed in chronically infected woodchucks treated by GS-9620, with confirmation of the long lasting off-drug effect (Menne et al, 2015). Following these studies, a phase-I clinical evaluation, aiming at evaluating the safety of this drug in human was initiated, and patients are now 19 being enrolled in a phase II trial combining tenofovir and GS-9620 in comparison to tenofovir monotherapy (Gane et al, 2015).…”

“…HBV-infected chimpanzees WHV-infected woodchuck Lanford et al, 2013;Menne et al, 2015. Interferon-(IFN-and its pegylated form are treat patients with chronic hepatitis B. IFN--based therapies result in -seroconversion in about 30% of cases. The same therapies result in g to antiin about 3% of cases.…”