Stephan Menne1, Daniel B Tumas2, Katherine H Liu3, Linta Thampi4, Dalal AlDeghaither4, Betty H Baldwin3, Christine A Bellezza3, Paul J Cote4, Jim Zheng5, Randall Halcomb6, Abigail Fosdick7, Simon P Fletcher2, Stephane Daffis2, Li Li8, Peng Yue8, Grushenka H I Wolfgang7, Bud C Tennant3. 1. Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States. Electronic address: sm923@georgetown.edu. 2. Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. 3. Department of Clinical Sciences, Gastrointestinal Unit, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States. 4. Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States. 5. Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. 6. Department of Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. 7. Department of Drug Safety Evaluation, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. 8. Department of Biomarkers, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
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 antiviral 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 6.2log10 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 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.
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 antiviral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to humanhepatitis 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 6.2log10 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 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.
Authors: Simon P Fletcher; Daniel J Chin; Yongmei Ji; A Leonardo Iniguez; Bruce Taillon; David C Swinney; Palanikumar Ravindran; Donavan T Cheng; Hans Bitter; Uri Lopatin; Han Ma; Klaus Klumpp; Stephan Menne Journal: Hepatology Date: 2012-07-12 Impact factor: 17.425
Authors: Robert E Lanford; Bernadette Guerra; Deborah Chavez; Luis Giavedoni; Vida L Hodara; Kathleen M Brasky; Abigail Fosdick; Christian R Frey; Jim Zheng; Grushenka Wolfgang; Randall L Halcomb; Daniel B Tumas Journal: Gastroenterology Date: 2013-02-13 Impact factor: 22.682
Authors: Uri Lopatin; Grushenka Wolfgang; Daniel Tumas; Christian R Frey; Carol Ohmstede; Joseph Hesselgesser; Brian Kearney; Lisa Moorehead; G Mani Subramanian; John G McHutchison Journal: Antivir Ther Date: 2013-02-15
Authors: Claire Dunn; Dimitra Peppa; Pooja Khanna; Gaia Nebbia; Meleri Jones; Nathan Brendish; R Monica Lascar; David Brown; Richard J Gilson; Richard J Tedder; Geoffrey M Dusheiko; Michael Jacobs; Paul Klenerman; Mala K Maini Journal: Gastroenterology Date: 2009-07-07 Impact factor: 22.682
Authors: Stephan Menne; Scott D Butler; Andrea L George; Ilia A Tochkov; Yuao Zhu; Shelly Xiong; John L Gerin; Paul J Cote; Bud C Tennant Journal: Antimicrob Agents Chemother Date: 2008-08-01 Impact factor: 5.191
Authors: Kira Rubtsova; Anatoly V Rubtsov; Linda F van Dyk; John W Kappler; Philippa Marrack Journal: Proc Natl Acad Sci U S A Date: 2013-08-06 Impact factor: 11.205
Authors: Katrin Schöneweis; Neil Motter; Pia L Roppert; Mengji Lu; Baoju Wang; Ingo Roehl; Dieter Glebe; Dongliang Yang; John D Morrey; Michael Roggendorf; Andrew Vaillant Journal: Antiviral Res Date: 2017-11-08 Impact factor: 5.970
Authors: So-Yon Lim; Christa E Osuna; Peter T Hraber; Joe Hesselgesser; Jeffrey M Gerold; Tiffany L Barnes; Srisowmya Sanisetty; Michael S Seaman; Mark G Lewis; Romas Geleziunas; Michael D Miller; Tomas Cihlar; William A Lee; Alison L Hill; James B Whitney Journal: Sci Transl Med Date: 2018-05-02 Impact factor: 17.956