A Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Dose and Multiple Doses of GSK3389404 in Chronic Hepatitis B Subjects

Inclusion Criteria: A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1.   Subject is able to understand and is capable of giving written informed consent, is willing to complywith protocol requirements, instructions and protocol-stated restrictions, and is likelyto complete the studyas planned.

2.   Between 18 and 70years of age, inclusive, at the time of signing the informed consent form.

3.   Abodymass index (BMI) between 18 to 30 kg/m2, inclusive.

4.   Male or female if theysatisfythe following:

a.   Females of reproductive potential are not permitted. Eligible females must meet the following criteria:

i.         Non-pregnant (as confirmed bya negative serum human chorionic gonadotrophin [hCG] test); AND

ii.       Non-lactating at screening and prior to dosing; AND

iii.       Non-reproductive potential as defined byat least one of the following conditions:

1.   Premenopausal females without reproductive potential defined by one of the following:

a.   Documented salpingectomy;

b.   Hysterectomy;

  c.   Documented bilateral oophorectomy.

2.   Postmenopausal defined as 12 months of spontaneous  

amenorrhea.            

 3.  A blood sample for simultaneous follicle-stimulating hormone (FSH) and estradiol levels maybe collected at the discretion of the investigator or site to confirm non- reproductive potential. Please refer to laboratoryreference ranges for confirmatorylevels for menopause.

b.        Male subjects with a female partner of child-bearing potential must agree to meet one of the contraception requirements from the time of first dose ofstudytreatment until the final Follow-up visit.

i.       Vasectomy

ii.       Male condom plus partner’s use of one of the contraceptive options below that meets the standard operating procedure (SOP) effectiveness criteria including a <1% rate of failure peryear, as stated in the product label:

1.    Contraceptive subdermal implant

2.    Intrauterine device or intrauterine system

3.    Combined estrogen and progestogen oral contraceptive

[Hatcher, 2011]

4.    Injectable progestogen [Hatcher, 2011]

5.    Contraceptive vaginal ring [Hatcher, 2011]

6.    Percutaneous contraceptive patches [Hatcher,2011]

These allowed methods of contraception are onlyeffective when used

consistently,correctlyand in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

5.   Documented chronic HBV infection, defined as positive plasma or serum HBsAg

≥6 months prior to screening.

6.   Subject with HBV treatment historyas follows:

a.    Part 1: Treatment naive or have had prior treatment with interferon (pegylated or non-pegylated) that must have ended at least 12 months prior to the Baseline visit (Day1pre-dose) and/or nucleos(t)ide analogue therapy that must have ended at least 6months prior to the Baseline visit.

b.    Part 2: Subjects with CHB receiving stable nucleos(t)ide analogue therapy, defined as no changes to their nucleos(t)ide regimen from at least

6 months prior to screening and with no planned changes to the stable regimen over the duration of thestudy.

7.   Plasmaor serum HBV DNA concentration:

a.    Part 1:

i.         ≥20,000IU/mL for HBeAg-positive subject ii.        ≥2000IU/mL for HBeAg-negative subjects

b.    Part 2: HBV DNA must be adequately suppressed, defined as plasma or serum HBV DNA <LLOQ.

8.   Plasma or serum HBsAg concentration >50IU/mL.

9.   Alanine aminotransferase (ALT) concentration:

a.    Part 1: ALT < 5 X ULN

b.    Part 2: ALT £ULN

ExclusionCriteria

A subject will not be eligible for inclusion in this studyif any of the following criteria apply:

1.     Medical history

a.    Historyof or active diagnosis of liver disease other than CHB, such as autoimmune hepatitis, non-alcoholic fattyliver disease/non-alcoholic steatohepatitis, hemochromatosis, or liver failure.

b.    Historyor other clinical evidence of hypertension, significant or unstable cardiacdisease (e.g., prolonged QT syndrome [torsade de pointes], angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia,coronaryheart disease and/or clinicallysignificant ECG abnormalities).

c.    Uncontrolled or historyof difficult to control hypertension.

d.    Historyof, or active diagnosis of, primaryorsecondaryrenal disease (e.g., renal disease secondarytodiabetes,hypertension, vascular disease, etc.).

e.    Historyof extrahepatic disorders possiblyrelated to HBV immune complexes (e.g., glomerulonephritis and polyarteritis nodosa).

f.     Historyof bleeding diathesis or coagulopathy. g.    Historyof or suspected presence of vasculitis. h.    Historyof Gilbert’s Syndrome.

i.     Historyofmalignancywithin the past 5years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer), subjects under evaluation for possible malignancyare not eligible.

2.    Historyof/sensitivityto GSK3389404 or components thereof or a historyof drug

or other allergythat,in the opinion of the investigator or medical monitor, contraindicates their participation.

3.    Confirmed or suspected HCC as evidenced by:

a.    Alpha-fetoprotein concentration ≥200 ng/mL. If the screening alpha- fetoprotein concentration is ≥50 ng/mLand <200ng/mL, the absence of liver mass must be documented byimaging within 6 months before randomization.

4.    Liver cirrhosis or evidence of cirrhosis as determined byanyof the following:

a.    Positive liver biopsy(i.e., Metavir Score F4) within 12 months of screening

b.    Fibroscan >12 kPa within 12 months of screening

c.    Aspartate aminotransferase (AST)-PlateletIndex(APRI) >2 and

FibroSure result >0.7 within 12 months of screening

For subjects without a test for cirrhosis in the above timeframes, APRI and

FibroSure should be performed during the screening period to rule out cirrhosis.

5.    A positive hepatitis C virus (HCV) antibodytest

6.    A positive human immunodeficiencyvirus(HIV)antibodytest

7.    Positive hepatitis D virus (HDV) antibodytest

8.    Laboratoryresults as follows:

a.    Total bilirubin concentration >1.25 XULN

b.    Serum albumin concentration <3.5 g/dL

c.    International normalized ratio (INR) >1.25 d.    Platelet count X109/L

e.    Serum creatinine concentration greater than the ULN

f.     Glomerular filtration rate (GFR) <90mL/minascalculatedbythe Chronic

KidneyDisease Epidemiologic Collaboration (CKD-EPI) formula.

Subjects with GFR L/min but ³ 80 mL/min maybe considered after consultation with the GSK medical monitor.

g.    Urine albumin to creatinine ratio (ACR)≥0.03 mg/mg. In the event of an ACR above this threshold, eligibilitymaybe confirmed bya second measurement

9.    Positive test for blood in urine. In the event of a positive test, the test maybe repeated once, and ifrepeat is negative or if urine microscopyreveals h-power field (HPF), the subject is considered eligible.

10.  Fridericia’s QT correction formula (QTcF) ≥450 msec (mean of triplicate measurements).

11.  Currentlytaking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy(≤2weeks).

12.  Current alcohol use as judged by investigator to potentiallyinterfere with participant compliance.

13.  A positive pre-studytreatment screen or an unwillingness to refrain from use of the illicit drugs and adhere to other protocol-stated restrictions while participating in the study.

14.  Where participation in the studywould result in donation of blood or blood products in excess of 500mLwithin a 56-dayperiod.

15.  The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing dayin the current study: 5 half-lives (if known) or twice the duration (if known) of the biological effect of the studytreatment (whichever is longer) or 90days(ifhalf- life or duration is unknown).

16.  Prior treatment with anyoligonucleotide or small interfering RNA (siRNA)

within 12 months prior to the first dosing day.