Chronic Hepatitis B

The primary objectives of this study are: • To evaluate the safety and tolerability of GS-9620 in adult subjects with chronic hepatitis B (CHB) infection who are currently not being treated • To evaluate the efficacy of GS-9620 as measured by the change from Baseline (BL) to Week 24 in serum Hepatitis B surface Antigen (HBsAg log10 IU/mL) levels

GS-9620,Tenofovir Disoproxil Fumarate (TDF)

GS-9620

tablet

1mg, 2mg 4mg

1. Efficacy:
The primary efficacy endpoint is the mean change (measured in log10 IU/mL) in serum HBsAg from Baseline to Week 24
The secondary efficacy endpoints are:
• Proportions of subjects with HBeAg loss and seroconversion at Weeks 24 and 48
• Proportions of subjects with HBsAg loss and seroconversion at Weeks 24 and 48
• The mean change (measured in log10 IU/mL) in serum HBsAg at Weeks 12 and 48
• Proportions of subjects with a ≥ 0.5 log10 IU/mL decline in serum HBsAg titers from Baseline at Weeks 12, 24 and 48
• Proportions of subjects with HBV DNA • Proportion of subjects experiencing virologic breakthrough (defined as confirmed HBV DNA ≥ 69 IU/mL after having been <69 IU/mL or confirmed HBV DNA ≥ 1 log10 IU/mL increase from nadir)
• Proportion of subjects with drug resistance mutations through Week 48
2. Safety: Adverse events (AEs) and clinical laboratory tests will be collected at
every visit and summarized through the study, including Treatment Free Follow-Up and Optional Treatment Extension Phase. The proportion of subjects in each treatment arm with an AE leading to early discontinuation of
study drug(s) and proportion of subjects with serious adverse events will be summarized through Weeks 24, 48, and the Optional Treatment Extension Phase.

Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible to participate in the study:
1 Must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
2 Adult male or non-pregnant female subjects, 18-65 years of age inclusive based on the date of the screening visit
3 Documented evidence of chronic HBV infection (e.g., documented HBsAg positive for more than 6 months)
4 Screening HBV DNA ≥ 2000 IU/mL
5 Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 6
6 Females of childbearing potential (as defined in Appendix 6) must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Baseline/Day 1 prior to randomization.
7 Willing to provide blood sample for TLR-7 and IL28B SNP assessment
8 Must be willing and able to comply with all study requirements

Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible to participate in the study:
1 Extensive bridging fibrosis or cirrhosis as defined clinically, by imaging or by the following:
a Metavir ≥ 3 or Ishak fibrosis score ≥ 4 by a liver biopsy within 1 year of screening, or, in the absence of an appropriate
liver biopsy, either:
b Screening FibroTest score of > 0.48 and APRI > 1, or
c FibroScan with a result > 9 kPa within ≤ 6 months of Baseline (if available)
d If liver biopsy is available, the liver biopsy result supersedes (b) and/or (c).
e If an appropriate liver biopsy is not available, fibrosis will be evaluated by (b) and/or (c), if available. In the event of
discordance between (b) and (c), the FibroScan results will take precedence.
2 Received oral antiviral (OAV) treatment for HBV within 3 months of screening
3 Received prolonged therapy with immune-modulators (e.g., corticosteroids) or biologics (e.g., monoclonal Ab,
interferon) within 3 months of screening
4 Subjects meeting any of the following laboratory parameters at screening:
a) White blood cell count < 2500 cell/mm
b) Neutrophil count < 1500 cell/mm3 (or < 1000 cell/mm3 if considered a physiological variant in a subject of African
descent)
c) ALT > 5x the upper limit of normal (ULN)
d) INR >ULN unless the subject is stable on anticoagulant regimen affecting INR
e) Albumin <3.9 g/dL
f) Total bilirubin >2 mg/dL
g) Platelet count <125,000 /mL
h) Estimate creatinine clearance (CLcr) <50 mL/min (using the Cockcroft-Gault method) based on serum creatinine and
actual body weight as measured at the screening evaluation 5 Co-infection with HCV, HIV or HDV
6 Evidence of hepatocellular carcinoma (e.g., as evidenced by recent imaging)
7 Any malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection
(e.g. basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are not eligible
8 Significant cardiovascular, pulmonary, or neurological disease
9 Any of the following conditions that may worsen in response to IFN:
a) Autoimmune disease (e.g. lupus erythematosus, rheumatoid
arthritis, inflammatory bowel disease, sarcoidosis, moderate
or severe psoriasis)
b) Poorly controlled diabetes mellitus
c) Significant psychiatric disorders
d) Thyroid disorder (unless controlled under treatment)
e) Pulmonary diseases (e.g. chronic obstructive pulmonary disease)
f) Retinal disease
g) Immunodeficiency disorders
10 Chronic liver disease of a non-HBV etiology
11 Received solid organ or bone marrow transplant
12 Use of investigational agents within 3 months of screening, unless allowed by the Sponsor
13 Use of any prohibited concomitant medications as described in Table 5-1
14 Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
15 Screening electrocardiogram (ECG) with clinically significant abnormalities, including QTcF interval (QT corrected using
Fridericia’s formula) ≥ 450 msec for males and ≥ 470 msec for females
16 Known hypersensitivity to study drugs, metabolites or formulation excipients
17 Lactating or pregnant females or those who may wish to become pregnant during the course of the study
18 Male subjects unwilling to refrain from sperm donation, or those intending to father a child, for at least 90 days after the last dose of GS-9620/Placebo and for at least 30 days after the lost dose of TDF
19 Believed by the Principal Investigator to be inappropriate for study participation for any reason