pteridines and Hepatitis B, Chronic studies

Hepatitis B, Chronic: INFLAMMATION of the LIVER in humans caused by HEPATITIS B VIRUS lasting six months or more. It is primarily transmitted by parenteral exposure, such as transfusion of contaminated blood or blood products, but can also be transmitted via sexual or intimate personal contact.

Research Excerpts

Excerpt	Relevance	Reference
"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."	6.87	Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. ( Ahn, SH; Brunetto, MR; Ferrari, C; Fung, S; Gaggar, A; Gane, EJ; Janssen, HLA; Joshi, A; Kim, YJ; Lau, AH; Massetto, B; Nguyen, AH; Subramanian, GM; Tsai, NCS; Woo, J; Yoshida, EM, 2018)
"1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity."	6.87	Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. ( Agarwal, K; Ahn, SH; Andreone, P; Bulusu, A; Cathcart, AL; Chuang, WL; Elkhashab, M; Gaggar, A; Kim, HJ; Lau, AH; Nguyen, MH; Subramanian, GM; Tian, X; Woo, J, 2018)
" Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days."	6.80	The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. ( Cheng, W; Coffin, CS; Fedorak, RN; Freilich, B; Gaggar, A; Gane, EJ; Garrison, KL; Gordon, SC; Kim, YJ; Kottilil, S; Lim, YS; Mani Subramanian, G; Massetto, B; McHutchison, JG; Pflanz, S; Roberts, S; Sicard, E; Visvanathan, K; Ye, Z, 2015)
"The oral Toll-like receptor (TLR) 7 agonist GS-9620 has antiviral effects in woodchuck and chimpanzee models of chronic hepatitis B virus (HBV) infection."	5.27	TLR7 Agonist Increases Responses of Hepatitis B Virus-Specific T Cells and Natural Killer Cells in Patients With Chronic Hepatitis B Treated With Nucleos(T)Ide Analogues. ( Alfieri, A; Boni, C; Brunetto, MR; Cavallone, D; Coco, B; Facchetti, F; Ferrari, C; Gaggar, A; Giuberti, T; Grossi, G; Laccabue, D; Lampertico, P; Lau, A; Mangia, A; Piazzolla, V; Rossi, M; Santoro, R; Subramanian, GM; Vecchi, A, 2018)
"GS-9620, an oral agonist of toll-like receptor 7, is in clinical development for the treatment of chronic hepatitis B (CHB)."	3.88	Anti-HBV response to toll-like receptor 7 agonist GS-9620 is associated with intrahepatic aggregates of T cells and B cells. ( Barry, V; Daffis, S; Delaney, WE; Fletcher, SP; French, DM; Huntzicker, E; Lanford, RE; Li, L; Mikaelian, I; Niu, C, 2018)
"GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB)."	3.88	Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism. ( Balsitis, S; Beran, RK; Bonnin, M; Chu, R; Daffis, S; Delaney, WE; Durantel, D; Fletcher, SP; Garg, AV; Li, L; Livingston, CM; Lucifora, J; Maadadi, S; Niu, C; Ramos, H; Salas, E; Zoulim, F, 2018)
"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."	2.87	Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. ( Ahn, SH; Brunetto, MR; Ferrari, C; Fung, S; Gaggar, A; Gane, EJ; Janssen, HLA; Joshi, A; Kim, YJ; Lau, AH; Massetto, B; Nguyen, AH; Subramanian, GM; Tsai, NCS; Woo, J; Yoshida, EM, 2018)
"1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity."	2.87	Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. ( Agarwal, K; Ahn, SH; Andreone, P; Bulusu, A; Cathcart, AL; Chuang, WL; Elkhashab, M; Gaggar, A; Kim, HJ; Lau, AH; Nguyen, MH; Subramanian, GM; Tian, X; Woo, J, 2018)
" Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days."	2.80	The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. ( Cheng, W; Coffin, CS; Fedorak, RN; Freilich, B; Gaggar, A; Gane, EJ; Garrison, KL; Gordon, SC; Kim, YJ; Kottilil, S; Lim, YS; Mani Subramanian, G; Massetto, B; McHutchison, JG; Pflanz, S; Roberts, S; Sicard, E; Visvanathan, K; Ye, Z, 2015)
"Because the course of chronic hepatitis B is determined by an ongoing interaction between the virus and the host immune system, immunomodulation may be the most logical approach in attempting to accomplish control or even cure of chronic hepatitis B."	2.52	How to achieve immune control in chronic hepatitis B? ( Janssen, HL; van Campenhout, MJ, 2015)

Research

Studies (12)

Authors

Clinical Trials (2)

Trial Overview

Trial Outcomes

Change From Baseline in Serum HBsAg Level at Week 12

Change From Baseline in Serum HBsAg Level at Week 4

Change From Baseline in Serum HBsAg Level at Week 48

Change From Baseline in Serum HBsAg Level at Week 8

Change From Baseline in Serum Hepatitis B Surface Antigen (HBsAg) Level at Week 24

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	0 (0.00)	29.6817
2010's	12 (100.00)	24.3611
2020's	0 (0.00)	2.80

Authors	Studies
Janssen, HLA	2
Brunetto, MR	2
Kim, YJ	2
Ferrari, C	2
Massetto, B	2
Nguyen, AH	1
Joshi, A	1
Woo, J	2
Lau, AH	2
Gaggar, A	4
Subramanian, GM	3
Yoshida, EM	1
Ahn, SH	2
Tsai, NCS	1
Fung, S	1
Gane, EJ	2
Li, L	2
Barry, V	1
Daffis, S	2
Niu, C	2
Huntzicker, E	1
French, DM	1
Mikaelian, I	1
Lanford, RE	2
Delaney, WE	2
Fletcher, SP	2
Lucifora, J	1
Bonnin, M	1
Maadadi, S	1
Salas, E	1
Chu, R	1
Ramos, H	1
Livingston, CM	1
Beran, RK	1
Garg, AV	1
Balsitis, S	1
Durantel, D	2
Zoulim, F	2
Boni, C	1
Vecchi, A	1
Rossi, M	1
Laccabue, D	1
Giuberti, T	1
Alfieri, A	1
Lampertico, P	1
Grossi, G	1
Facchetti, F	1
Coco, B	1
Cavallone, D	1
Mangia, A	1
Santoro, R	1
Piazzolla, V	1
Lau, A	1
Agarwal, K	2
Elkhashab, M	1
Bulusu, A	1
Tian, X	1
Cathcart, AL	1
Andreone, P	1
Kim, HJ	1
Chuang, WL	1
Nguyen, MH	2
Younossi, ZM	1
Stepanova, M	1
Younossi, I	1
Papatheodoridis, G	1
Gane, E	1
Tsai, N	1
Nader, F	1
Guerra, B	1
Chavez, D	1
Giavedoni, L	1
Hodara, VL	1
Brasky, KM	1
Fosdick, A	1
Frey, CR	1
Zheng, J	2
Wolfgang, G	1
Halcomb, RL	2
Tumas, DB	2
Luangsay, S	1
Roethle, PA	1
McFadden, RM	1
Yang, H	1
Hrvatin, P	1
Hui, H	1
Graupe, M	1
Gallagher, B	1
Chao, J	1
Hesselgesser, J	1
Duatschek, P	1
Lu, B	1
Perry, J	1
Lim, YS	1
Gordon, SC	1
Visvanathan, K	1
Sicard, E	1
Fedorak, RN	1
Roberts, S	1
Ye, Z	1
Pflanz, S	1
Garrison, KL	1
Mani Subramanian, G	1
McHutchison, JG	1
Kottilil, S	1
Freilich, B	1
Coffin, CS	1
Cheng, W	1
van Campenhout, MJ	1
Janssen, HL	1
Lamb, C	1
Arbuthnot, P	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Safety and Efficacy of GS-9620 for the Treatment of Virally-Suppressed Subjects With Chronic Hepatitis B[NCT02166047]	Phase 2	162 participants (Actual)	Interventional	2014-06-30	Completed
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Safety and Efficacy of GS-9620 in Combination With Tenofovir Disoproxil Fumarate (TDF) for the Treatment of Subjects With Chronic Hepatitis B and Who Are Currently[NCT02579382]	Phase 2	192 participants (Actual)	Interventional	2015-11-10	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Intervention	log10 IU/mL (Mean)
Vesatolimod 1 mg 4 Weeks (Cohort A)	-0.050
Vesatolimod 2 mg 4 Weeks (Cohort A)	0.017
Vesatolimod 4 mg 4 Weeks (Cohort A)	-0.004
Placebo 4 Weeks (Cohort A)	-0.023
Vesatolimod 1 mg 8 Weeks (Cohort B)	-0.031
Vesatolimod 2 mg 8 Weeks (Cohort B)	-0.005
Vesatolimod 4 mg 8 Weeks (Cohort B)	-0.021
Placebo 8 Weeks (Cohort B)	-0.020
Vesatolimod 1 mg 12 Weeks (Cohort C)	-0.023
Vesatolimod 2 mg 12 Weeks (Cohort C)	-0.034
Vesatolimod 4 mg 12 Weeks (Cohort C)	-0.010
Placebo 12 Weeks (Cohort C)	-0.024

Intervention	log10 IU/mL (Mean)
Vesatolimod 1 mg 4 Weeks (Cohort A)	-0.009
Vesatolimod 2 mg 4 Weeks (Cohort A)	0.025
Vesatolimod 4 mg 4 Weeks (Cohort A)	-0.008
Placebo 4 Weeks (Cohort A)	-0.017
Vesatolimod 1 mg 8 Weeks (Cohort B)	-0.003
Vesatolimod 2 mg 8 Weeks (Cohort B)	0.014
Vesatolimod 4 mg 8 Weeks (Cohort B)	-0.001
Placebo 8 Weeks (Cohort B)	0.046
Vesatolimod 1 mg 12 Weeks (Cohort C)	-0.034
Vesatolimod 2 mg 12 Weeks (Cohort C)	-0.023
Vesatolimod 4 mg 12 Weeks (Cohort C)	-0.001
Placebo 12 Weeks (Cohort C)	-0.041

Intervention	log10 IU/mL (Mean)
Vesatolimod 1 mg 4 Weeks (Cohort A)	-0.048
Vesatolimod 2 mg 4 Weeks (Cohort A)	-0.055
Vesatolimod 4 mg 4 Weeks (Cohort A)	-0.071
Placebo 4 Weeks (Cohort A)	-0.067
Vesatolimod 1 mg 8 Weeks (Cohort B)	-0.035
Vesatolimod 2 mg 8 Weeks (Cohort B)	-0.024
Vesatolimod 4 mg 8 Weeks (Cohort B)	-0.114
Placebo 8 Weeks (Cohort B)	-0.324
Vesatolimod 1 mg 12 Weeks (Cohort C)	-0.083
Vesatolimod 2 mg 12 Weeks (Cohort C)	-0.071
Vesatolimod 4 mg 12 Weeks (Cohort C)	-0.054
Placebo 12 Weeks (Cohort C)	-0.063

Intervention	log10 IU/mL (Mean)
Vesatolimod 1 mg 4 Weeks (Cohort A)	-0.029
Vesatolimod 2 mg 4 Weeks (Cohort A)	0.002
Vesatolimod 4 mg 4 Weeks (Cohort A)	-0.035
Placebo 4 Weeks (Cohort A)	-0.013
Vesatolimod 1 mg 8 Weeks (Cohort B)	0.000
Vesatolimod 2 mg 8 Weeks (Cohort B)	0.006
Vesatolimod 4 mg 8 Weeks (Cohort B)	0.020
Placebo 8 Weeks (Cohort B)	0.006
Vesatolimod 1 mg 12 Weeks (Cohort C)	-0.021
Vesatolimod 2 mg 12 Weeks (Cohort C)	-0.033
Vesatolimod 4 mg 12 Weeks (Cohort C)	-0.013
Placebo 12 Weeks (Cohort C)	-0.019

A mixed effect model for repeated measures (MMRM) was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement. (NCT02166047)
Timeframe: Baseline to Week 24

Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and Seroconversion at Week 24

Intervention	log10 IU/mL (Least Squares Mean)
Vesatolimod 1 mg 4 Weeks (Cohort A)	-0.011
Vesatolimod 2 mg 4 Weeks (Cohort A)	0.033
Vesatolimod 4 mg 4 Weeks (Cohort A)	-0.018
Placebo 4 Weeks (Cohort A)	-0.035
Vesatolimod 1 mg 8 Weeks (Cohort B)	-0.081
Vesatolimod 2 mg 8 Weeks (Cohort B)	-0.081
Vesatolimod 4 mg 8 Weeks (Cohort B)	-0.082
Placebo 8 Weeks (Cohort B)	-0.163
Vesatolimod 1 mg 12 Weeks (Cohort C)	-0.015
Vesatolimod 2 mg 12 Weeks (Cohort C)	0.000
Vesatolimod 4 mg 12 Weeks (Cohort C)	0.000
Placebo 12 Weeks (Cohort C)	0.001

"HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit within the targeted time window.~HBsAg seroconversion was defined as qualitative hepatitis B surface antibody (HBsAb) result changing from negative at baseline to positive at any postbaseline visit within the targeted time window.~Participants who had missing information were assumed to have no HBsAg loss and no HBsAg seroconversion." (NCT02166047)
Timeframe: Week 24

Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and Seroconversion at Week 48

Intervention	percentage of participants (Number)
Vesatolimod 1 mg 4 Weeks (Cohort A)	0
Vesatolimod 2 mg 4 Weeks (Cohort A)	0
Vesatolimod 4 mg 4 Weeks (Cohort A)	0
Placebo 4 Weeks (Cohort A)	0
Vesatolimod 1 mg 8 Weeks (Cohort B)	0
Vesatolimod 2 mg 8 Weeks (Cohort B)	0
Vesatolimod 4 mg 8 Weeks (Cohort B)	0
Placebo 8 Weeks (Cohort B)	0
Vesatolimod 1 mg 12 Weeks (Cohort C)	0
Vesatolimod 2 mg 12 Weeks (Cohort C)	0
Vesatolimod 4 mg 12 Weeks (Cohort C)	0
Placebo 12 Weeks (Cohort C)	0

Composite Endpoint Measuring the Percentage of Participants With Hepatitis B Envelope Antigen (HBeAg) Loss and Seroconversion at Week 24

Intervention	percentage of participants (Number)
Vesatolimod 1 mg 4 Weeks (Cohort A)	0.0
Vesatolimod 2 mg 4 Weeks (Cohort A)	0.0
Vesatolimod 4 mg 4 Weeks (Cohort A)	0.0
Placebo 4 Weeks (Cohort A)	0.0
Vesatolimod 1 mg 8 Weeks (Cohort B)	0.0
Vesatolimod 2 mg 8 Weeks (Cohort B)	0.0
Vesatolimod 4 mg 8 Weeks (Cohort B)	0.0
Placebo 8 Weeks (Cohort B)	0.0
Vesatolimod 1 mg 12 Weeks (Cohort C)	0.0
Vesatolimod 2 mg 12 Weeks (Cohort C)	0.0
Vesatolimod 4 mg 12 Weeks (Cohort C)	0.0
Placebo 12 Weeks (Cohort C)	0.0

"HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit within the targeted time window.~HBeAg seroconversion was defined as qualitative hepatitis B envelope antibody (HBeAb) result changing from negative at baseline to positive at any postbaseline visit within the targeted time window.~Participants who had missing information were assumed to have no HBeAg loss and no HBeAg seroconversion." (NCT02166047)
Timeframe: Week 24

Composite Endpoint Measuring the Percentage of Participants With Hepatitis B Envelope Antigen (HBeAg) Loss and Seroconversion at Week 48

Intervention	percentage of participants (Number)
Vesatolimod 1 mg 4 Weeks (Cohort A)	0.0
Vesatolimod 2 mg 4 Weeks (Cohort A)	0.0
Vesatolimod 4 mg 4 Weeks (Cohort A)	0.0
Placebo 4 Weeks (Cohort A)	0.0
Vesatolimod 1 mg 8 Weeks (Cohort B)	20.0
Vesatolimod 2 mg 8 Weeks (Cohort B)	0.0
Vesatolimod 4 mg 8 Weeks (Cohort B)	0.0
Vesatolimod 1 mg 12 Weeks (Cohort C)	0.0
Vesatolimod 2 mg 12 Weeks (Cohort C)	0.0
Vesatolimod 4 mg 12 Weeks (Cohort C)	0.0
Placebo 12 Weeks (Cohort C)	0.0

Mean Change (Measured in log10 IU/mL) in HBsAg From Baseline at Week 12

Mean Change (Measured in log10 IU/mL) in HBsAg From Baseline at Week 48

Mean Change (Measured in log10 IU/mL) in Hepatitis B Surface Antigen (HBsAg) From Baseline at Week 24

Intervention	percentage of participants (Number)
Vesatolimod 1 mg 4 Weeks (Cohort A)	0.0
Vesatolimod 2 mg 4 Weeks (Cohort A)	0.0
Vesatolimod 4 mg 4 Weeks (Cohort A)	0.0
Placebo 4 Weeks (Cohort A)	0.0
Vesatolimod 1 mg 8 Weeks (Cohort B)	20.0
Vesatolimod 2 mg 8 Weeks (Cohort B)	0.0
Vesatolimod 4 mg 8 Weeks (Cohort B)	0.0
Vesatolimod 1 mg 12 Weeks (Cohort C)	33.3
Vesatolimod 2 mg 12 Weeks (Cohort C)	0.0
Vesatolimod 4 mg 12 Weeks (Cohort C)	0.0
Placebo 12 Weeks (Cohort C)	0.0

Intervention	log10 IU/mL (Mean)
TDF + Placebo	-0.087
TDF + Vesatolimod 1 mg	-0.041
TDF + Vesatolimod 2 mg	-0.138
TDF + Vesatolimod 4 mg	-0.020

Intervention	log10 IU/mL (Mean)
TDF + Placebo	-0.338
TDF + Vesatolimod 1 mg	-0.079
TDF + Vesatolimod 2 mg	-0.197
TDF + Vesatolimod 4 mg	-0.088

The change from baseline to Week 24 in HBsAg (log10 IU/mL) was analyzed using a mixed model for repeated measures (MMRM). The model included treatment, baseline HBsAg (log10 IU/mL), baseline Hepatitis B Envelope Antigen (HBeAg) status (positive or negative), baseline alanine aminotransferase (ALT) level relative to upper limit of normal (ULN) (> 19 vs ≤ 19 IU/L for females; > 30 vs ≤ 30 IU/L for males), visit and treatment-by-visit interaction as fixed effects, and visit as a repeated measure. (NCT02579382)
Timeframe: Baseline; Week 24

Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase/Reverse Transcriptase (Pol/RT)

Intervention	log10 IU/mL (Least Squares Mean)
TDF + Placebo	-0.163
TDF + Vesatolimod 1 mg	-0.056
TDF + Vesatolimod 2 mg	-0.146
TDF + Vesatolimod 4 mg	-0.036

Sequence analysis of the HBV pol/RT was attempted for any participant who had HBV DNA ≥ 69 IU/mL at Week 48 or early discontinuation. Results of the alignment of Week 48 and baseline sequence were reported as a change from baseline sequence. (NCT02579382)
Timeframe: Baseline; Week 48

Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 12

Intervention	Participants (Count of Participants)
TDF + Placebo	2
TDF + Vesatolimod 1 mg	4
TDF + Vesatolimod 2 mg	2
TDF + Vesatolimod 4 mg	2

HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 12 post-baseline visit. Missing values were considered failures. (NCT02579382)
Timeframe: Baseline to Week 12

Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 24

Intervention	percentage of participants (Number)
TDF + Placebo	7.1
TDF + Vesatolimod 1 mg	3.8
TDF + Vesatolimod 2 mg	10.7
TDF + Vesatolimod 4 mg	1.8

HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 24 post-baseline visit. (NCT02579382)
Timeframe: Baseline to Week 24

Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 48

Intervention	percentage of participants (Number)
TDF + Placebo	10.7
TDF + Vesatolimod 1 mg	3.8
TDF + Vesatolimod 2 mg	10.7
TDF + Vesatolimod 4 mg	3.6

Percentage of Participants With HBeAg Loss and Seroconversion at Week 24

Intervention	percentage of participants (Number)
TDF + Placebo	17.9
TDF + Vesatolimod 1 mg	5.7
TDF + Vesatolimod 2 mg	16.1
TDF + Vesatolimod 4 mg	14.5

HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit. HBeAg seroconversion was defined as qualitative Hepatitis B Envelope Antibody (HBeAb) result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis. (NCT02579382)
Timeframe: Week 24

Percentage of Participants With HBeAg Loss and Seroconversion at Week 48

Intervention	percentage of participants (Number)
TDF + Placebo	0
TDF + Vesatolimod 1 mg	0
TDF + Vesatolimod 2 mg	0
TDF + Vesatolimod 4 mg	0

HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit. HBeAg seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis. (NCT02579382)
Timeframe: Week 48

Percentage of Participants With HBsAg Loss and Seroconversion at Week 24

Intervention	percentage of participants (Number)
TDF + Placebo	0
TDF + Vesatolimod 1 mg	5.0
TDF + Vesatolimod 2 mg	4.3
TDF + Vesatolimod 4 mg	4.8

HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit. HBsAg seroconversion was defined as qualitative Hepatitis B Surface Antibody (HBsAb) result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis. (NCT02579382)
Timeframe: Week 24

Percentage of Participants With HBsAg Loss and Seroconversion at Week 48

Intervention	percentage of participants (Number)
TDF + Placebo	0
TDF + Vesatolimod 1 mg	0
TDF + Vesatolimod 2 mg	0
TDF + Vesatolimod 4 mg	0

HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit. HBsAg seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis. (NCT02579382)
Timeframe: Week 48

Percentage of Participants With HBV DNA < LLOQ at Week 48

Intervention	percentage of participants (Number)
TDF + Placebo	0
TDF + Vesatolimod 1 mg	0
TDF + Vesatolimod 2 mg	0
TDF + Vesatolimod 4 mg	0

LLOQ for HBV DNA was defined as 20 IU/mL. The participants with missing information were excluded from the analysis. (NCT02579382)
Timeframe: Week 48

Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantitation (LLOQ) at Week 24

Intervention	percentage of participants (Number)
TDF + Placebo	64.3
TDF + Vesatolimod 1 mg	62.3
TDF + Vesatolimod 2 mg	75.9
TDF + Vesatolimod 4 mg	75.5

LLOQ for HBV DNA was defined as 20 IU/mL. The participants with missing information were excluded from the analysis. (NCT02579382)
Timeframe: Week 24

Pharmacokinetic (PK) Parameter: AUClast of Vesatolimod

Intervention	percentage of participants (Number)
TDF + Placebo	53.6
TDF + Vesatolimod 1 mg	58.5
TDF + Vesatolimod 2 mg	59.3
TDF + Vesatolimod 4 mg	63.0

AUClast is defined as the area under the concentration versus time curve from time zero to the last quantifiable concentration. (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

PK Parameter: %AUCexp of Vesatolimod

Intervention	hourpicogram/milliliter (hpg/mL) (Mean)
TDF + Vesatolimod 1 mg	5252.3
TDF + Vesatolimod 2 mg	7170.6
TDF + Vesatolimod 4 mg	28537.2

%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf. (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

PK Parameter: AUCinf of Vesatolimod

Intervention	Percentage of AUC (Mean)
TDF + Vesatolimod 1 mg	31.1
TDF + Vesatolimod 2 mg	28.6
TDF + Vesatolimod 4 mg	19.3

AUCinf is defined as the concentration of drug extrapolated to infinite time. (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

PK Parameter: CL/F of Vesatolimod

Intervention	h*pg/mL (Mean)
TDF + Vesatolimod 1 mg	7277.3
TDF + Vesatolimod 2 mg	10239.0
TDF + Vesatolimod 4 mg	34534.8

CL/F is defined as the apparent oral clearance following administration of the drug. (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

PK Parameter: Clast of Vesatolimod

Intervention	liter/hour (Mean)
TDF + Vesatolimod 1 mg	273.9
TDF + Vesatolimod 2 mg	262.3
TDF + Vesatolimod 4 mg	156.2

Clast is defined as the last observable concentration of drug. (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

PK Parameter: Cmax of Vesatolimod

Intervention	pg/mL (Mean)
TDF + Vesatolimod 1 mg	92.8
TDF + Vesatolimod 2 mg	119.0
TDF + Vesatolimod 4 mg	328.0

Cmax is defined as the maximum concentration of drug. (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

PK Parameter: T1/2 of Vesatolimod

Intervention	picogram/milliliter (pg/mL) (Mean)
TDF + Vesatolimod 1 mg	667.8
TDF + Vesatolimod 2 mg	850.4
TDF + Vesatolimod 4 mg	4957.5

T1/2 is defined as the estimate of the terminal elimination half-life of the drug. (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

PK Parameter: Tlast of Vesatolimod

Intervention	hours (Median)
TDF + Vesatolimod 1 mg	10.79
TDF + Vesatolimod 2 mg	14.12
TDF + Vesatolimod 4 mg	13.32

Tlast is defined as the time (observed time point) of Clast. (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

PK Parameter: Tmax of Vesatolimod

Intervention	hours (Median)
TDF + Vesatolimod 1 mg	24.00
TDF + Vesatolimod 2 mg	24.00
TDF + Vesatolimod 4 mg	24.00

Tmax is defined as the time (observed time point) of Cmax (NCT02579382)
Timeframe: Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose

Percentage of Participants Experiencing Virologic Breakthrough

Intervention	hours (Median)
TDF + Vesatolimod 1 mg	1.00
TDF + Vesatolimod 2 mg	2.00
TDF + Vesatolimod 4 mg	3.00

Virologic breakthrough was defined as confirmed HBV DNA ≥ 69 IU/mL after having had HBV DNA < 69 IU/mL or confirmed 1.0 log10 IU/mL or greater increase in HBV DNA from nadir. Confirmation requires 2 consecutive occurrences of elevation in HBV DNA to > 69 IU/mL after having had HBV DNA < 69 IU/mL or 1.0 log10 IU/mL or greater increases in HBV DNA from nadir. (NCT02579382)
Timeframe: Weeks 24 and 48

Article	Year
How to achieve immune control in chronic hepatitis B? Hepatology international, 2015, Volume: 9, Issue:1 Topics: Antiviral Agents; Biomarkers; DNA, Circular; DNA, Viral; Hepatitis B Surface Antigens; Hepatitis B v	2015
Activating the innate immune response to counter chronic hepatitis B virus infection. Expert opinion on biological therapy, 2016, Volume: 16, Issue:12 Topics: Animals; Antiviral Agents; DNA Replication; DNA, Viral; Hepatitis B virus; Hepatitis B, Chronic; Hum	2016

Article	Year
Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. Journal of hepatology, 2018, Volume: 68, Issue:3 Topics: Adaptive Immunity; Administration, Oral; Adult; Antiviral Agents; Double-Blind Method; Drug Monitori	2018
TLR7 Agonist Increases Responses of Hepatitis B Virus-Specific T Cells and Natural Killer Cells in Patients With Chronic Hepatitis B Treated With Nucleos(T)Ide Analogues. Gastroenterology, 2018, Volume: 154, Issue:6 Topics: Adult; Antiviral Agents; Female; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chron	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, 2018, Volume: 25, Issue:11 Topics: Adult; Aged; Antiviral Agents; Cytokines; DNA, Viral; Double-Blind Method; Drug Therapy, Combination	2018
Patient-reported outcomes in patients chronic viral hepatitis without cirrhosis: The impact of hepatitis B and C viral replication. Liver international : official journal of the International Association for the Study of the Liver, 2019, Volume: 39, Issue:10 Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis B, Chronic; Hepatitis C, Chron	2019
The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. Journal of hepatology, 2015, Volume: 63, Issue:2 Topics: Administration, Oral; Adolescent; Adult; Aged; Antiviral Agents; DNA, Viral; Dose-Response Relations	2015

Article	Year
Anti-HBV response to toll-like receptor 7 agonist GS-9620 is associated with intrahepatic aggregates of T cells and B cells. Journal of hepatology, 2018, Volume: 68, Issue:5 Topics: Animals; Antiviral Agents; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Aggregation; Disease Mode	2018
Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism. Journal of hepatology, 2018, Volume: 68, Issue:5 Topics: Animals; Antigen Presentation; Antiviral Agents; Cells, Cultured; Cytokines; DNA, Circular; DNA, Vir	2018
GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology, 2013, Volume: 144, Issue:7 Topics: Administration, Oral; Animals; Antiviral Agents; Hepatitis B virus; Hepatitis B, Chronic; Immunity,	2013
Targeting innate immunity: a new step in the development of combination therapy for chronic hepatitis B. Gastroenterology, 2013, Volume: 144, Issue:7 Topics: Animals; Antiviral Agents; Hepatitis B virus; Hepatitis B, Chronic; Immunologic Factors; Pteridines;	2013
Identification and optimization of pteridinone Toll-like receptor 7 (TLR7) agonists for the oral treatment of viral hepatitis. Journal of medicinal chemistry, 2013, Sep-26, Volume: 56, Issue:18 Topics: Administration, Oral; Animals; Antiviral Agents; Dogs; Drug Evaluation, Preclinical; Female; Hepatit	2013

Intervention	percentage of participants (Number)
	Week 24	Week 48
TDF + Placebo	0	0
TDF + Vesatolimod 1 mg	0	3.8
TDF + Vesatolimod 2 mg	1.8	1.8
TDF + Vesatolimod 4 mg	0	0

pteridines and Hepatitis B, Chronic