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

This Phase 1/2a multiple part study is a first time-in-human (FTIH) study designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of single (Part 1) and repeat doses (Part 2) of GSK3965193 in healthy participants. Part 3 will evaluate the ability of GSK3965193 to lower hepatitis B virus surface antigen (HBsAg) in participants living with chronic hepatitis B infection (PLWCHB) and will be given the option to subsequently receive treatment with open label bepirovirsen. Part 4 will evaluate the safety and tolerability of combination therapy with GSK3965193 and bepirovirsen and the potential to effect sustained virologic response in PLWCHB.

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 of signing the informed consent. * Body weight \>=50 kilograms (kg) and body mass index within the range 18-32 kilograms per square meter (kg/m\^2) (inclusive). * Male or female participant: a. Parts 1 and 2: woman of nonchildbearing potential only. b. Parts 3 and 4: woman of nonchildbearing potential or woman of child-bearing potential who is not pregnant or breastfeeding and is using a contraceptive method that 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 \>=6 months 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 \1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \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 peripheral neuropathy. 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 before screening and/or have a smoking pack history of \>5 pack years Exclusion Criteria for PLWCHB: * Clinically significant abnormalities affecting physical or mental health in medical history 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 cancers that are cured by surgical resection (e.g., skin cancer). * History of vasculitis or presence of symptoms and signs of potential vasculitis \[e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause\] or history/presence of other diseases Exclusion Criteria for Healthy Participants: * Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M \[IgM\]), or positive for HBV, 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 if bilirubin is fractionated and direct bilirubin \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 peripheral neuropathy. 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 before screening and/or have a smoking pack history of \>5 pack years Exclusion Criteria for PLWCHB: * Clinically significant abnormalities affecting physical or mental health in medical history 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 cancers that are cured by surgical resection (e.g., skin cancer). * History of vasculitis or presence of symptoms and signs of potential vasculitis \[e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause\] or history/presence of other diseases that may be associated with vasculitis 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 by investigator to potentially interfere with participant compliance. b. History of or current drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance. * History or other evidence of bleeding from esophageal varices. * Documented history or other evidence of metabolic liver disease within 1 year of randomization. * 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 oral corticosteroids, interferon or pegylated interferon) within the 3 months prior to randomization or the expectation that such treatment will be needed at any time during the study. * Abnormal and clinically significant 12-lead ECG finding. * Currently taking, or taken within 3 months prior to randomization, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (≤2 weeks) or topical/inhaled steroid use. * Participants requiring anti-coagulation therapies. * Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 12 months prior to the first dosing day. * Positive test for COVID-19 infection.