Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B

Harry L.A. Janssen, Maurizia R. Brunetto, Yoon Jun Kim, Carlo Ferrari, Benedetta Massetto, Anh Hoa Nguyen, Adarsh Joshi, Jacky Woo, Audrey H. Lau, Anuj Gaggar, G. Mani Subramanian, Eric M. Yoshida, SangHoon Ahn, Naoky C.S. Tsai, Scott Fung, Edward J. Gane

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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 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 (log 10 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.

Original languageEnglish
Pages (from-to)431-440
Number of pages10
JournalJournal of Hepatology
Volume68
Issue number3
DOIs
Publication statusPublished - 2018 Mar 1

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Chronic Hepatitis B
Hepatitis B Surface Antigens
Safety
Hepatitis B e Antigens
Hepatitis B virus
Interferon-alpha
Antiviral Agents
Toll-Like Receptor 7
Placebos
Therapeutics
Adaptive Immunity
GS-9620
Serum
Innate Immunity
Interferons
Multivariate Analysis
Biomarkers
Clinical Trials
Cytokines
Gene Expression

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Janssen, H. L. A., Brunetto, M. R., Kim, Y. J., Ferrari, C., Massetto, B., Nguyen, A. H., ... Gane, E. J. (2018). Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. Journal of Hepatology, 68(3), 431-440. https://doi.org/10.1016/j.jhep.2017.10.027
Janssen, Harry L.A. ; Brunetto, Maurizia R. ; Kim, Yoon Jun ; Ferrari, Carlo ; Massetto, Benedetta ; Nguyen, Anh Hoa ; Joshi, Adarsh ; Woo, Jacky ; Lau, Audrey H. ; Gaggar, Anuj ; Subramanian, G. Mani ; Yoshida, Eric M. ; Ahn, SangHoon ; Tsai, Naoky C.S. ; Fung, Scott ; Gane, Edward J. / Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. In: Journal of Hepatology. 2018 ; Vol. 68, No. 3. pp. 431-440.
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title = "Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B",
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 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 (log 10 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.",
author = "Janssen, {Harry L.A.} and Brunetto, {Maurizia R.} and Kim, {Yoon Jun} and Carlo Ferrari and Benedetta Massetto and Nguyen, {Anh Hoa} and Adarsh Joshi and Jacky Woo and Lau, {Audrey H.} and Anuj Gaggar and Subramanian, {G. Mani} and Yoshida, {Eric M.} and SangHoon Ahn and Tsai, {Naoky C.S.} and Scott Fung and Gane, {Edward J.}",
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Janssen, HLA, Brunetto, MR, Kim, YJ, Ferrari, C, Massetto, B, Nguyen, AH, Joshi, A, Woo, J, Lau, AH, Gaggar, A, Subramanian, GM, Yoshida, EM, Ahn, S, Tsai, NCS, Fung, S & Gane, EJ 2018, 'Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B', Journal of Hepatology, vol. 68, no. 3, pp. 431-440. https://doi.org/10.1016/j.jhep.2017.10.027

Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. / Janssen, Harry L.A.; Brunetto, Maurizia R.; Kim, Yoon Jun; Ferrari, Carlo; Massetto, Benedetta; Nguyen, Anh Hoa; Joshi, Adarsh; Woo, Jacky; Lau, Audrey H.; Gaggar, Anuj; Subramanian, G. Mani; Yoshida, Eric M.; Ahn, SangHoon; Tsai, Naoky C.S.; Fung, Scott; Gane, Edward J.

In: Journal of Hepatology, Vol. 68, No. 3, 01.03.2018, p. 431-440.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B

AU - Janssen, Harry L.A.

AU - Brunetto, Maurizia R.

AU - Kim, Yoon Jun

AU - Ferrari, Carlo

AU - Massetto, Benedetta

AU - Nguyen, Anh Hoa

AU - Joshi, Adarsh

AU - Woo, Jacky

AU - Lau, Audrey H.

AU - Gaggar, Anuj

AU - Subramanian, G. Mani

AU - Yoshida, Eric M.

AU - Ahn, SangHoon

AU - Tsai, Naoky C.S.

AU - Fung, Scott

AU - Gane, Edward J.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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 (log 10 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.

AB - 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 (log 10 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.

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