This study will assess the safety, efficacy and immune response following the sequential treatment of GlaxoSmithKline's (GSK) ASO compound (GSK3228836) and CHB-TI (GSK3528869A) in participants 18 to 65 years stable on NA treatment for CHB. The aim is to quantify the efficacy of sequential therapy as well as to determine an added value of sequential therapy over GSK3228836 therapy in CHB patients treated with NAs. In addition, the study will assess the effect of different treatment durations of GSK3228836 (12 or 24 weeks) prior to initiating GSK3528869A treatment.

The study follow-up period was reduced from 2 years post last dose to at least 1 year post last dose, with Visit Treatment 2-Day 505 defined as the last visit of the study. For participants who completed visits Treatment 2-Day 673 or Treatment 2-Day 841, those visits were considered the last study visit.

Inclusion criteria:

• Participants, who, in the opinion of the investigator, can and will comply with the requirements of the protocol.

• Written or witnessed/thumb printed informed consent obtained from the participant prior to performance of any study-specific procedure.

• A male or female between, and including, 18 and 65 years of age at the time of signing of the informed consent (except for South Korea, where a male or female between, and including, 19 and 65 years of age at the time of signing of the informed consent can participate in the study).

• Participants who are Hepatitis B envelop antigen (HBeAg) positive or negative.

• Participants who have documented chronic HBV infection >=6 months prior to screening and currently stable on NA 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 the study.

• CHB patient, under and adherent to treatment with a NA with high barrier to resistance (e.g. entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide).

• Participants with ALT <=2x upper limit of normal (ULN) (i.e., no ALT >2x ULN) documented in approximately the last 6 months.

• Participants with plasma or serum HBsAg concentration >100 IU/mL.

• Participants must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.

• A male participant is eligible if he agrees to the following during the intervention period and for at least 90 days after the last dose of study intervention:

  • Refrain from donating sperm
  • AND be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed below.
  • Agree to use a male condom [and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak] when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.

• A female participant is eligible:

  • If she is not pregnant or breastfeeding
  • AND at least one of the following conditions applies:
  • Is not a WOCBP
  • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and for at least 90 days after the last dose of study treatment.

• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.

Exclusion criteria:

Medical conditions

• Clinically significant abnormalities, aside from chronic HBV infection.

• Co-infection with:

  • Current or past history of HCV
  • HIV
  • HDV

• History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by:

  • both AST-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7
  • Liver biopsy (METAVIR Score F4) or Liver stiffness >12 kPa

• FibroScan TE score >9.6 kPa and FibroTest score >0.59 at Screening.

• Diagnosed or suspected HCC.

• History of:

  • malignancy within the past 5 years except of specific cancers that are cured by surgical resection
  • vasculitis or presence of symptoms and signs of potential vasculitis
  • extrahepatic disorders possibly related to HBV immune conditions

• Positive (or borderline positive) ANCA at screening.

• Low C3/C4 at screening AND evidence of past history or current manifestations of vasculitic/inflammatory/autoimmune conditions.

• History of alcohol or drug abuse/dependence.

• QTcF >=450 msec.

• Laboratory results as follows:

  • Serum albumin <3.5 g/dL
  • GFR <60 mL/min/1.73m^2
  • INR >1.25
  • PLT count <140x10^9/L
  • HGB <10 g/dl
  • T Bil >1.25xULN unless considered as clinically not significant by the Investigator
  • ACR >=0.03 mg/mg

• Medical history of hepatic decompensation.

• Planned or previous liver transplantation.

• Documented evidence of other currently active cause of hepatitis.

• Any other clinical condition that might pose additional risk to the participant due to participation in the study.

• Major congenital defects.

• Recurrent history or uncontrolled neurological disorders or seizures.

• History of any reaction or hypersensitivity likely to be exacerbated by any component of the study intervention(s).

Prior/Concomitant therapy

• Use of any investigational or non-registered product other than the study interventions within 30 days before the first dose of study interventions, or their planned use during the study.

• Use of systemic cytotoxic agents, chronic antiviral agents or Chinese herbal medicines which may have activity against HBV within 6 months prior the study.

• Currently taking, or took within 12 months of screening, any interferon-containing therapy.

• Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 months, except for adenovirus/adenovector-based COVID-19 vaccines that could be administered up to 30 days prior to the first study vaccine dose (applicable for all patients except for the patients in France) OR Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 months (applicable for the patients in France only).

• Planned administration/administration of a vaccine not foreseen by the study protocol within 14 days before the first dose and/or 30 days after the last dose of study intervention administration, with the exception of influenza vaccine that may be given at any time except within a 7-day period before or after each dose and COVID-19 vaccine that may be given at any time except within a 30-day period before or after each vaccine dose apart from COVID-19 mRNA based-vaccines that may be administered any time except for the period of 14 days before and 30 days after each study vaccine dose.

• Administration of:

  • long-acting immune-modifying drugs at any time during the study
  • immunoglobulins and/or any blood products or plasma derivatives within 3 months before the first dose of study interventions or planned administration during the study

• Chronic administration of immunosuppressants or other immune-modifying drugs within 3 months prior to the first study intervention (e.g. prednisone equivalent >=20 mg/day; >=10 mg/day applicable in Germany only). Inhaled and topical steroids are allowed.

• Participants for whom immunosuppressive treatment is not advised.

• Treatment with nephrotoxic drugs or competitors of renal excretion within 2 months prior to Screening or planned during the study.

• Participants requiring anti-coagulation therapies.

Prior/Concurrent clinical study experience

• Concurrently participating in another clinical study, at any time during the study period, in which the participant has been/will be exposed to an investigational/a non-investigational intervention.
• Previous participation in clinical trials with administration of either GSK3228836 or GSK3528869A.
• Previous participation in a clinical study in which he/she has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives or twice the duration of the biological effect of the study treatment or 90 days.
• Prior treatment with any other oligonucleotide/siRNA within 12 months prior to the first dosing day.

Other exclusions:

• Pregnant or lactating female.
• Female planning to become pregnant/to discontinue contraceptive precautions.
• Any study personnel or their immediate dependents, family, or household members.
• History of/sensitivity to GSK3228836, or components thereof, or a history of drug or other allergy that contraindicates their participation.

IPD for this study will be made available via the Clinical Study Data Request site.

IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.

Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Open-label for Treatment 1 and single-blinded for Treatment 2.