Evaluation of Safety, Efficacy, and Immunogenicity of Sequential Bepirovirsen and GSKVX000000008866 in Chronic Hepatitis B Patients on Nucleos(t)ide Analogue Therapy

Trial ID: 2024-512352-38-00
Protocol: 217023
Sponsor: GlaxoSmithKline Biologicals

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Diseases & Conditions

Chronic hepatitis B Hepatitis B

Objectives

The primary objective of this study is to evaluate the **safety** and **efficacy** of sequential treatment with GSK3228836 and GSK3528869A in participants with chronic Hepatitis B (CHB) infection who are stable on nucleos(t)ide analogue (NA) therapy. This is clinically relevant as it aims to determine the potential of these treatments to improve patient outcomes by reducing viral load and enhancing safety profiles in a population already receiving standard therapy.

Secondary objectives include:

Assessing the safety of the sequential treatment in participants with CHB infection who are virally suppressed on NA therapy.
Evaluating the efficacy of the treatment in comparison with baseline in virally suppressed participants.
Describing the durability of sustained virologic response (SVR).
Assessing the humoral and cellular immune responses specific to HBs and HBc antigens following the sequential treatment.

Participants

The clinical trial involves a total of **109 participants** diagnosed with **Chronic Hepatitis B** who are stable on nucleos(t)ide analogue (NA) therapy. The study population includes both male and female subjects, aged between 18 and 65 years, with a specific age range adjustment for participants from South Korea, where the minimum age is 19 years. Participants were selected based on their documented chronic HBV infection for at least six months prior to screening and their stability on NA therapy, with no changes to their regimen for at least six months before screening and no planned changes during the study. The trial includes individuals who are either HBeAg positive or negative, with an Alanine Transaminase (ALT) level of ≤2x the upper limit of normal, and a plasma or serum HBsAg concentration greater than 100 IU/mL. Participants must also have adequately suppressed HBV DNA levels, defined as less than 90 IU/mL. The trial population is characterized by adherence to a stable NA regimen with a high barrier to resistance, such as entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide. Lifestyle considerations include the requirement for male participants to refrain from donating sperm and to use contraception or maintain abstinence from heterosexual intercourse during the intervention period and for at least 90 days after the last dose. Female participants must not be pregnant or breastfeeding and must use a highly effective contraceptive method if they are of childbearing potential. The trial does not specifically exclude vulnerable populations, indicating inclusivity in the selection process.

Plans and Procedures

The clinical trial is a **phase II**, single-blinded, randomized, controlled, multi-country study designed to evaluate the safety, reactogenicity, efficacy, and immune response of sequential treatment with an anti-sense oligonucleotide (ASO) against **chronic Hepatitis B** (CHB), followed by CHB-targeted immunotherapy (CHB-TI) in patients receiving nucleos(t)ide analogue (NA) therapy. The trial involves the administration of **bepirovirsen** as a solution for injection via subcutaneous use, and other investigational products as suspensions for injection via intramuscular use. The study is expected to last until February 11, 2026, with recruitment having commenced on March 31, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, documented chronic HBV infection, and stability on NA therapy. The trial will include follow-up visits to monitor safety and efficacy endpoints, such as the percentage of participants reporting any grade 3 adverse events (AEs) or serious adverse events (SAEs) from the first dose of GSK3228836 up to the study end. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 24 weeks, depending on the treatment regimen.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial aims to provide comprehensive data on the safety and efficacy of the sequential treatment regimen, contributing to the understanding of therapeutic strategies for managing chronic Hepatitis B.

Treatment

The clinical trial involves the administration of **bepirovirsen**, an experimental medication formulated as a **solution for injection**. This medication is administered via **subcutaneous use**. The dosage is set at a maximum of 300 mg per day, with a total maximum dose of 7800 mg over a treatment period of 24 weeks. Bepirovirsen is a nucleic acid-based substance developed by GlaxoSmithKline, identified by the sponsor product code GSK3228836B. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another experimental treatment in the study is a vaccine identified by the active substance code **GSKVX000000008866**. This vaccine is provided as a **suspension for injection** and is administered via **intramuscular use**. The maximum daily and total dose is 0.5 ml, with a treatment period of 1 day. This vaccine is developed by GlaxoSmithKline Biologicals S.A. and is identified by the sponsor product code GSKVx000000005626.

The trial also includes a second vaccine with the active substance code **GSKVX000000009151**, also formulated as a **suspension for injection** for **intramuscular use**. The dosing regimen is identical to the previous vaccine, with a maximum daily and total dose of 0.5 ml over a 1-day treatment period. This vaccine is also developed by GlaxoSmithKline Biologicals S.A., with the sponsor product code GSKVx000000005680.

Additionally, the study involves a vaccine containing two active substances, **GSKVX000000008885** and **GSKVX000000017033**. This vaccine is administered as a **suspension for injection** via **intramuscular use**. The dosing schedule allows for a maximum daily dose of 0.5 ml and a total dose of 1 ml over a 2-day treatment period. This vaccine is developed by GlaxoSmithKline Biologicals S.A. and is identified by the sponsor product code GSKVx000000016714.

The trial also utilizes a non-experimental treatment, the **Buffer S9b Solution for suspension for injection**, which serves as a placebo or comparator treatment. This solution is not associated with any specific pharmaceutical form or active substance and is used to maintain the study's control conditions.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the percentage of participants who achieve a **Sustained Virologic Response (SVR)**, defined as Hepatitis B surface antigen (HBsAg) levels below the lower limit of quantification (LLOQ) and Hepatitis B virus (HBV) DNA levels below the LLOQ. The trial will compare the efficacy of sequential treatment with GSK3228836 and GSK3528869A against GSK3228836 alone in participants with chronic Hepatitis B (CHB) infection who are stable on nucleos(t)ide analogue (NA) therapy.

Secondary efficacy endpoints include the number of participants with a ≥0.5 log decrease, ≥1-log decrease, HBsAg loss, and log-changes from baseline in quantitative HBsAg (qHBsAg). Additionally, the number of participants achieving HBsAg loss and anti-HBs seroconversion will be measured. The mean qHBsAg will also be evaluated. The duration of SVR will be assessed by measuring the time to the first occurrence of HBsAg reversion and HBV DNA reversion. Virologic breakthrough will be defined as an HBV DNA increase of ≥1-log from nadir or HBV DNA becoming quantifiable after being below the LLOQ.

Immunogenicity assessments will include responder rates and concentrations of anti-HBc and anti-HBs antibodies at predefined time points. The frequency of HBc- and HBs-specific CD4+ T-cell and CD8+ T-cell responses will also be evaluated, including CD4+ and CD8+ T-cell responder rates.

Inclusion and Exclusion Criteria

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Inclusion Criteria

"• Participants, who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits). • 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 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 Alanine Transaminase (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 to participate if they agree 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 o 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 to participate:  If she is not pregnant or breastfeeding  AND at least one of the following conditions applies: o Is not a WOCBP o 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."

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Exclusion Criteria

"Medical conditions • Clinically significant abnormalities, aside from chronic HBV infection in medical history • Co-infection with:  Current or past history of Hepatitis C virus (HCV)  Human immunodeficiency virus (HIV)  Hepatitis D virus (HDV) • History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by  both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7  Regardless of APRI or Fibrosure/FibroTest score, if the participant meets one of the following historical criteria, they will be excluded from the study o Liver biopsy (i.e., METAVIR Score F4) o Liver stiffness >12 kPa • FibroScan TE score >9.6 kPa and FibroTest score >0.59 at Screening. • Diagnosed or suspected HCC as evidenced by the following:  Alpha-fetoprotein concentration ≥200 ng/mL  If the screening alpha-fetoprotein concentration is ≥50 ng/mL and <200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomisation. • History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection. • History of vasculitis or presence of symptoms and signs of potential vasculitis. • History of extrahepatic disorders possibly related to HBV immune conditions. • Positive (or borderline positive) Anti-neutrophil cytoplasmic antibody (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 • Fridericia’s QT correction formula (QTcF) ≥450 msec • Laboratory results as follows:  Serum albumin <3.5 g/dL  Glomerular filtration rate (GFR) <60 mL/ min /1.73m2 as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula  INR >1.25  Platelet count <140x109/L  Haemoglobin< 10 g/dl  Total bilirubin >1.25xULN  Urine albumin to creatinine ratio (ACR) ≥0.03 mg/mg (or ≥30 mg/g). • Medical history of hepatic decompensation. • Planned for liver transplantation or previous liver transplantation. • Documented evidence of other currently active cause of hepatitis • Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the participant due to participation in the study. • Major congenital defects, as assessed by the Investigator. • 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 (drug, vaccine or medical device) other than the study interventions during the period beginning 30 days before the first dose of study interventions, or their planned use during the study period. • Use of systemic cytotoxic agents, chronic antiviral agents or Chinese herbal medicines which may have activity against HBV within the previous 6 months. • 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 Coronavirus Disease 2019 (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/product not foreseen by the study protocol in the period starting 14 days before the first dose and ending 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 messenger ribonucleic acid (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 period (e.g. infliximab). • Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 3 months before the administration of the first dose of study interventions or planned administration during the study period. • Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 3 months prior to the first study intervention dose(s). For corticosteroids, this will mean prednisone equivalent ≥20 mg/day for adult participants (≥10 mg/day applicable in Germany only). Inhaled and topical steroids are allowed. • Participants for whom immunosuppressive treatment is not advised, including therapeutic doses of corticosteroids, will be excluded. • Treatment with nephrotoxic drugs or competitors of renal excretion within 2 months prior to Screening. • 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 or will be exposed to an investigational or a non-investigational intervention (drug/invasive medical device). • 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 (if known) or twice the duration (if known) of the biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown). • Prior treatment with any other oligonucleotide or small interfering RNA (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."

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	31 Mar 2022	2
Bulgaria	Not Recruiting	31 Mar 2022	15
France	Not Recruiting	31 Mar 2022	10
Germany	Not Recruiting	31 Mar 2022	12
Italy	Not Recruiting	31 Mar 2022	10
Poland	Not Recruiting	31 Mar 2022	18
Romania	Not Recruiting	31 Mar 2022	14
Spain	Not Recruiting	31 Mar 2022	15