Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection

Inclusion Criteria:

Parts 1 and 2: Participants between 18 and 55 years of age inclusive, at the time of signing the informed consent.

• Parts 3 and 4: Participants between 18 and 65 years of age inclusive, at the time ofsigning the informed consent.

• Body weight >=50 kilograms (kg) and body mass index within the range 18-32 kilogramsper square meter (kg/m^2) (inclusive).

• Male or female participant: a. Parts 1 and 2: woman of nonchildbearing potentialonly. b. Parts 3 and 4: woman of nonchildbearing potential or woman of child-bearingpotential who is not pregnant or breastfeeding and is using a contraceptive methodthat is highly effective.

• Capable of giving signed informed consent.

• Additional Inclusion Criteria for PLWCHB (Parts 3 and 4).

• Participants who have documented chronic hepatitis B virus (HBV) infection >=6months prior to screening.

• Participants currently receiving stable NA therapy (e.g., tenofovir disoproxil,tenofovir alafenamide, entecavir).

• Plasma or serum HBsAg concentration >100 IU/mL.

• Plasma or serum HBV deoxyribonucleic acid (DNA) concentration <90 IU/mL.

• Hepatitis B virus e-antigen (HBeAg) positive or negative.

• Alanine aminotransferase (ALT) <=2 times the upper limit of normal (ULN)

Exclusion Criteria:

Exclusion Criteria for Healthy Participants:

• Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M [IgM]), or positive forHBV, hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening

• A current diagnosis of migraine headache

• ALT >1 times ULN.

• Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable ifbilirubin is fractionated and direct bilirubin <35 percent [%])

• Corrected QT interval (QTc) >450 milliseconds (msec)

• Signs and symptoms suggestive of Coronavirus Disease 2019 (COVID-19)

• Participants with known COVID-19 positive contacts in the past 14 days.

• For participants in Part 2A: i. Personal history or family history of peripheralneuropathy. ii. A score ≥4 on the Toronto clinical scoring system for polyneuropathy

• Current or previous use of tobacco- or nicotine-containing products (for example (e.g.) cigarettes, nicotine patches or electronic devices) within 6 months beforescreening and/or have a smoking pack history of >5 pack years

Exclusion Criteria for PLWCHB:

• Clinically significant abnormalities affecting physical or mental health in medicalhistory or on physical examination, aside from chronic HBV infection.

• Co-infection with or past history of HCV, HIV or Hepatitis D virus (HDV).

• History of or suspected liver cirrhosis and/or evidence of cirrhosis.

• Diagnosed or suspected hepatocellular carcinoma.

• History of malignancy within the past 5 years with the exception of specific cancersthat are cured by surgical resection (e.g., skin cancer).

• History of vasculitis or presence of symptoms and signs of potential vasculitis [e.g., vasculitic rash, skin ulceration, repeated blood detected in urine withoutidentified cause] or history/presence of other diseases Exclusion Criteria forHealthy Participants:

• Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M [IgM]), or positive forHBV, hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening.

• A current diagnosis of migraine headache

• ALT >1 times ULN.

• Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable ifbilirubin is fractionated and direct bilirubin <35 percent [%]).

• Corrected QT interval (QTc) >450 milliseconds (msec).

• Signs and symptoms suggestive of Coronavirus Disease 2019 (COVID-19).

• Participants with known COVID-19 positive contacts in the past 14 days.

• For participants in Part 2A: i. Personal history or family history of peripheralneuropathy. ii. A score ≥4 on the Toronto clinical scoring system forpolyneuropathy.

• Current or previous use of tobacco- or nicotine-containing products (for example (e.g.) cigarettes, nicotine patches or electronic devices) within 6 months beforescreening and/or have a smoking pack history of >5 pack years

Exclusion Criteria for PLWCHB:

• Clinically significant abnormalities affecting physical or mental health in medicalhistory or on physical examination, aside from chronic HBV infection.

• Co-infection with or past history of HCV, HIV or Hepatitis D virus (HDV).

• History of or suspected liver cirrhosis and/or evidence of cirrhosis.

• Diagnosed or suspected hepatocellular carcinoma.

• History of malignancy within the past 5 years with the exception of specific cancersthat are cured by surgical resection (e.g., skin cancer).

• History of vasculitis or presence of symptoms and signs of potential vasculitis [e.g., vasculitic rash, skin ulceration, repeated blood detected in urine withoutidentified cause] or history/presence of other diseases that may be associated withvasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis,relapsing polychondritis, mononeuritis multiplex).

• History of extrahepatic disorders possibly related to HBV immune conditions (e.g.,nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa,cryoglobulinaemia, uncontrolled hypertension).

• History of alcohol or drug abuse/dependence: a. Current alcohol use as judged byinvestigator to potentially interfere with participant compliance. b. History of orcurrent drug abuse/dependence as judged by the investigator to potentially interferewith participant compliance.

• History or other evidence of bleeding from esophageal varices.

• Documented history or other evidence of metabolic liver disease within 1 year ofrandomization.

• Personal history or family history of peripheral neuropathy.

• A score >4 on the Toronto clinical scoring system for polyneuropathy.

• History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oralcorticosteroids, interferon or pegylated interferon) within the 3 months prior torandomization or the expectation that such treatment will be needed at any timeduring the study.

• Abnormal and clinically significant 12-lead ECG finding.

• Currently taking, or taken within 3 months prior to randomization, anyimmunosuppressing drugs (e.g., prednisone), other than a short course of therapy (≤2weeks) or topical/inhaled steroid use.

• Participants requiring anti-coagulation therapies.

• Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 12months prior to the first dosing day.

• Positive test for COVID-19 infection.