Chronic Hepatitis B Infection

The primary objectives of this study are as follows: • To evaluate the safety and tolerability of GS-4774 in subjects with chronic hepatitis B infection (CHB) • To evaluate the efficacy of GS-4774 at Week 24 as measured by mean change (measured in log10 IU/mL) in serum Hepatitis B surface Antigen (HBsAg) from Baseline (BL) The secondary objectives of this study are as follows: • To evaluate the mean change (measured in log10 IU/mL) in serum HBsAg from Baseline (BL) to Weeks 12 and 48 • To evaluate the proportion of subjects with HBsAg loss and seroconversion at Weeks 24 and 48 • To evaluate the proportion of subjects with a ≥ 0.5 log10 or a ≥ 1.0 log10 decline in HBsAg at Weeks 12, 24, and 48 • To evaluate the proportion of subjects with Hepatitis B envelope Antigen (HBeAg) loss and seroconversion at Weeks 24 and 48 • To evaluate proportion of subjects with HBV DNA <20 IU/mL at Week 24 and 48 • To evaluate the proportion of subjects experiencing virologic breakthrough • To evaluate the incidence of drug resistance mutations at Week 48

GS-4774 Powder for Suspension for Injection

GS-4774 (a therapeutic vaccine comprised of recombinant yeast)

Powder for Suspension for Injection

24

The primary efficacy endpoint of this study is:
*The mean change in serum Hepatitis B surface antigen (HBsAg) from Baseline to
Week 24 (measured in log10 IU/mL)

The secondary efficacy endpoints of this study are:
*The mean change in serum HBsAg from Baseline to Weeks 12 and 48 (measured in
log10 IU/mL)
*The proportions of subjects with HBsAg loss and HBsAg seroconversion at Weeks 24
and 48
*The proportions of subjects with a ≥ 0.5 log10 or a ≥ 1.0 log10 decline in HBsAg at
Weeks 12, 24, and 48
*The proportions of subjects with HBeAg loss and HBeAg seroconversion at Weeks 24
and 48
*The proportions of subjects with HBV DNA <20 IU/mL at Weeks 24 and 48
*The proportion of subjects experiencing virologic breakthrough at Weeks 24 and 48
*The incidence of drug resistance mutations at Week 48

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, which must be obtained prior to initiation of study procedures
2. Adult male or non-pregnant, non-lactating female subjects, ≥18 years of age, 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. The Body mass index (BMI) must be ≥ 18 kg/m2
6. 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
7. Lactating females must agree to discontinue nursing before the Investigational Medicinal Product (IMP) is administered
8. A negative serum pregnancy test is required for female subjects (unless surgically sterile or greater than two years post-menopausal)
9. Must be willing and able to comply with all study requirements

Subjects who meet any of the following exclusion criteria are not eligible to participate in the study.
1. Cirrhosis and advanced bridging fibrosis as defined clinically, histologically, or by imaging, including:
• Ishak fibrosis score ≥4 by a liver biopsy within 1 year of screening, and in the absence of an appropriate liver biopsy, either
• Screening FibroTest score of >0.48 and APRI of >1, or
• Fibroscan with a result >9 kPa within ≤6 months of screening
In the event of discordant results between non-invasive methods, the Fibroscan result will take precedence
2. Subjects meeting any of the following laboratory parameters at screening:
• ALT >5x the upper limit of normal (ULN)
• INR >1.5 unless the subject is stable on anticoagulant regimen affecting INR
• Albumin <3.5 g/dL
• Total bilirubin >2 mg/dL
• Platelet count <100,000 /mL
• 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
3. Co-infection with HCV, HIV or HDV
4. Received antiviral treatment for HBV within 3 months of screening
5. Evidence of hepatocellular carcinoma (e.g., as evidenced by recent imaging)
6. Significant cardiovascular, pulmonary, or neurological disease
7. Women who may wish to become pregnant during the course of the study
8. Male subjects unwilling to refrain from sperm donation for at least 90 days after the last dose of GS-4774
9. Received solid organ or bone marrow transplant
10. Received prolonged therapy with immunomodulators (e.g., corticosteroids) or biologics (e.g., monoclonal Ab, interferon) within 3 months of screening
11. Use of investigational agents within 3 months of screening
12. Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
13. Receipt of immunoglobulin or other blood products within 3 months prior to enrollment
14. History of demyelinating disease (Guillain-Barre), Bell’s Palsy, Crohn’s disease, Ulcerative colitis, or automimmune disease
15. Documented history of yeast allergy
16. Known hypersensitivity to study drugs, metabolites or formulation excipients
17. Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for possible malignancy are not eligible
18. Believed by the study Investigator to be inappropriate for study participation for any reason