Harry L A Janssen1, Maurizia R Brunetto2, Yoon Jun Kim3, Carlo Ferrari4, Benedetta Massetto5, Anh-Hoa Nguyen5, Adarsh Joshi5, Jacky Woo5, Audrey H Lau5, Anuj Gaggar5, G Mani Subramanian5, Eric M Yoshida6, Sang Hoon Ahn7, Naoky C S Tsai8, Scott Fung9, Edward J Gane10. 1. Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada. Electronic address: harry.janssen@uhn.ca. 2. Clinical and Experimental Medicine Department, University of Pisa, Pisa, Italy. 3. Seoul National University Hospital, Seoul, Republic of Korea. 4. Università Degli Studi di Parma, Italy. 5. Gilead Sciences, Inc., Foster City, CA, United States. 6. The University of British Columbia, Vancouver, Canada. 7. Yonsei University College of Medicine, Seoul, Republic of Korea. 8. John A. Burns School of Medicine, University of Hawaii, Manoa, United States. 9. Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada. 10. Auckland Clinical Studies Ltd, Auckland, New Zealand.
Abstract
BACKGROUND & AIMS:Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment. METHODS: In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified byhepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation. RESULTS: The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex. CONCLUSIONS: Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed. LAY SUMMARY: In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.
RCT Entities:
BACKGROUND & AIMS:Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment. METHODS: In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation. RESULTS: The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex. CONCLUSIONS:Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed. LAY SUMMARY: In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBVpatients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.
Authors: Gregory Q Del Prete; W Gregory Alvord; Yuan Li; Claire Deleage; Mukta Nag; Kelli Oswald; James A Thomas; Cathi Pyle; William J Bosche; Vicky Coalter; Adam Wiles; Rodney Wiles; Brian Berkemeier; Michael Hull; Elizabeth Chipriano; Lorna Silipino; Randy Fast; Jacob Kiser; Rebecca Kiser; Tyler Malys; Joshua Kramer; Matthew W Breed; Charles M Trubey; Jacob D Estes; Tiffany L Barnes; Joseph Hesselgesser; Romas Geleziunas; Jeffrey D Lifson Journal: JCI Insight Date: 2019-06-06
Authors: Peter A Revill; Francis V Chisari; Joan M Block; Maura Dandri; Adam J Gehring; Haitao Guo; Jianming Hu; Anna Kramvis; Pietro Lampertico; Harry L A Janssen; Massimo Levrero; Wenhui Li; T Jake Liang; Seng-Gee Lim; Fengmin Lu; M Capucine Penicaud; John E Tavis; Robert Thimme; Fabien Zoulim Journal: Lancet Gastroenterol Hepatol Date: 2019-04-10