Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment

K. Agarwal, S. H. Ahn, M. Elkhashab, A. H. Lau, A. Gaggar, A. Bulusu, X. Tian, A. L. Cathcart, J. Woo, G. M. Subramanian, P. Andreone, H. J. Kim, W. L. Chuang, M. H. Nguyen

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.

Original languageEnglish
Pages (from-to)1331-1340
Number of pages10
JournalJournal of Viral Hepatitis
Volume25
Issue number11
DOIs
Publication statusPublished - 2018 Nov

Fingerprint

Chronic Hepatitis B
Antiviral Agents
Safety
Hepatitis B Surface Antigens
Hepatitis B e Antigens
Tenofovir
Therapeutics
Interferons
Toll-Like Receptor 7
Placebos
Hepatitis B Antibodies
GS-9620
Serum
Alanine Transaminase
Human Influenza
Cytokines
DNA
Genes

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Infectious Diseases
  • Virology

Cite this

Agarwal, K. ; Ahn, S. H. ; Elkhashab, M. ; Lau, A. H. ; Gaggar, A. ; Bulusu, A. ; Tian, X. ; Cathcart, A. L. ; Woo, J. ; Subramanian, G. M. ; Andreone, P. ; Kim, H. J. ; Chuang, W. L. ; Nguyen, M. H. / Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. In: Journal of Viral Hepatitis. 2018 ; Vol. 25, No. 11. pp. 1331-1340.
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abstract = "Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1{\%}) and HBeAg-negative (60.9{\%}) at baseline. Among vesatolimod-treated patients, most (60.4{\%}-69.1{\%}) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.",
author = "K. Agarwal and Ahn, {S. H.} and M. Elkhashab and Lau, {A. H.} and A. Gaggar and A. Bulusu and X. Tian and Cathcart, {A. L.} and J. Woo and Subramanian, {G. M.} and P. Andreone and Kim, {H. J.} and Chuang, {W. L.} and Nguyen, {M. H.}",
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Agarwal, K, Ahn, SH, Elkhashab, M, Lau, AH, Gaggar, A, Bulusu, A, Tian, X, Cathcart, AL, Woo, J, Subramanian, GM, Andreone, P, Kim, HJ, Chuang, WL & Nguyen, MH 2018, 'Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment', Journal of Viral Hepatitis, vol. 25, no. 11, pp. 1331-1340. https://doi.org/10.1111/jvh.12942

Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. / Agarwal, K.; Ahn, S. H.; Elkhashab, M.; Lau, A. H.; Gaggar, A.; Bulusu, A.; Tian, X.; Cathcart, A. L.; Woo, J.; Subramanian, G. M.; Andreone, P.; Kim, H. J.; Chuang, W. L.; Nguyen, M. H.

In: Journal of Viral Hepatitis, Vol. 25, No. 11, 11.2018, p. 1331-1340.

Research output: Contribution to journalArticle

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T1 - Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment

AU - Agarwal, K.

AU - Ahn, S. H.

AU - Elkhashab, M.

AU - Lau, A. H.

AU - Gaggar, A.

AU - Bulusu, A.

AU - Tian, X.

AU - Cathcart, A. L.

AU - Woo, J.

AU - Subramanian, G. M.

AU - Andreone, P.

AU - Kim, H. J.

AU - Chuang, W. L.

AU - Nguyen, M. H.

PY - 2018/11

Y1 - 2018/11

N2 - Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.

AB - Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.

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