Efficacy and Safety of Bepirovirsen in Nucleos(t)ide Analogue-Treated Patients with Chronic Hepatitis B: A Phase 3 Randomized, Double-Blind Study

Trial ID: 2023-504238-23-00
Protocol: 219288
Sponsor: Glaxosmithkline Research & Development Limited

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Diseases & Conditions

Chronic hepatitis B

Objectives

The primary objective of this Phase 3 multicenter, randomized, double-blind study is to evaluate the **treatment effect** of 24 weeks of bepirovirsen, administered with loading doses, in achieving a functional cure in participants with **chronic Hepatitis B virus (HBV) infection** who are on nucleos(t)ide analogue (NA) treatment and have a baseline HBsAg level of ≤3000 IU/mL. This objective is clinically relevant as it aims to determine the potential of bepirovirsen to provide a functional cure for chronic HBV, a condition that can lead to serious liver complications if not effectively managed.

Participants

The clinical trial involves a total of **694 participants** diagnosed with **chronic Hepatitis B**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults. Participants were selected based on their documented chronic HBV infection for at least six months prior to screening and are currently on stable nucleos(t)ide analogue (NA) therapy. The trial does not include a vulnerable population. Participants are required to have a plasma or serum HBsAg concentration greater than 100 IU/mL but not exceeding 3000 IU/mL, and their HBV DNA concentration must be adequately suppressed, defined as less than 90 IU/mL. Additionally, their alanine aminotransferase (ALT) levels should be no more than twice the upper limit of normal. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided further details on the selection process or additional lifestyle factors.

Plans and Procedures

The clinical trial is a **Phase 3**, multicenter, randomized, double-blind study designed to evaluate the efficacy and safety of **bepirovirsen** in participants with **chronic hepatitis B** who are currently receiving nucleos(t)ide analogue (NA) treatment. The trial aims to achieve a functional cure in participants with a baseline HBsAg concentration of ≤3000 IU/mL over a treatment period of 24 weeks. The study involves the administration of bepirovirsen as a **solution for injection** via subcutaneous use, with a maximum daily dose of 300 mg and a total dose of 7800 mg. A placebo group will be included for comparison.

The trial is expected to last until June 2026, with recruitment having commenced in December 2022. Participants will be involved in the study for a period of 24 weeks, with the possibility of early termination if they do not adhere to the protocol, experience adverse effects, or if the study is discontinued for any reason. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as documented chronic HBV infection for at least six months, stable NA therapy, and specific HBsAg and HBV DNA concentrations. Follow-up visits will be conducted to monitor the participants' response to treatment and any adverse events. The end-of-study visit will assess the primary endpoint of achieving a functional cure 24 weeks after discontinuation of all chronic HBV treatment, including bepirovirsen, placebo, and NA, without the use of rescue medication.

Treatment

The clinical trial involves the administration of **bepirovirsen**, an investigational medication developed by GlaxoSmithKline. Bepirovirsen is formulated as a **solution for injection** and is administered via the **subcutaneous route**. The dosing regimen includes a maximum daily dose of 300 mg, with a total maximum dose of 7800 mg over a treatment period of 24 weeks. The active substance, bepirovirsen, is of nucleic acid origin, and the pharmaceutical form is specifically designed for injection purposes. The trial aims to evaluate the efficacy and safety of bepirovirsen in participants with chronic Hepatitis B Virus (HBV) infection who are already receiving nucleos(t)ide analogue treatment.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in the study. The placebo is designed to match the bepirovirsen solution for injection in appearance and administration method, ensuring the double-blind nature of the trial. The placebo does not contain any active substance and serves to provide a control for assessing the true efficacy of bepirovirsen. The administration schedule for the placebo mirrors that of the active treatment, maintaining consistency in dosing frequency and route of administration.

Efficacy

The efficacy of the treatment in this clinical trial will be assessed primarily through the achievement of a **functional cure** for 24 weeks following the discontinuation of all chronic Hepatitis B Virus (HBV) treatments, including bepirovirsen, placebo, and nucleos(t)ide analogues (NA), without the use of rescue medication. This endpoint is designed to evaluate the long-term effectiveness of bepirovirsen in participants with chronic HBV infection who are already receiving stable NA therapy. The trial is structured as a Phase 3, multicenter, randomized, double-blind study, ensuring rigorous assessment of the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participants who have documented chronic HBV infection ≥6 months prior to screening and currently receiving stable NA therapy defined as no changes to their NA regimen from at least 6 months prior to Screening and with no planned changes to the stable regimen over the duration of the study.
Plasma or serum HBsAg concentration >100 IU/mL and HBsAg concentration ≤3000 IU/mL
Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.
Alanine aminotransferase (ALT) ≤2 × upper limit of normal (ULN).
Participants who are willing and able to cease their NA treatment in accordance with the protocol.
Male and/or female

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Exclusion Criteria

Clinically significant abnormalities, aside from chronic HBV infection in medical history (e.g., moderate-severe liver disease other than chronic HBV, acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening, significant/unstable cardiac disease, uncontrolled diabetes, bleeding diathesis or coagulopathy) or clinically significant physical examination findings.
"Co-infection with: a) Hepatitis C infection or participants that have been cured for <12 months at the time of screening b) Human immunodeficiency virus (HIV), c) Hepatitis D virus."
"History of or suspected liver cirrhosis and/or evidence of cirrhosis. Diagnosed or suspected hepatocellular carcinoma. History of malignancy within the past 5 years except for specific cancers that are cured by surgical resection (e.g., skin cancer). Participants under evaluation for possible malignancy are not eligible. 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) current or history of an autoimmune condition 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, cryoglobulinemia, uncontrolled hypertension). History of alcohol or drug abuse/dependence. Currently taking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (≤2 weeks) or topical/inhaled steroid use. Participants to whom immunosuppressive treatment, including therapeutic doses of steroids is contraindicated, should not be considered for enrolment in the study. Currently taking, or has taken within 12 months of Screening, any interferon containing therapy. Participants requiring anti coagulation therapies (e.g., warfarin, Factor Xa inhibitors) or anti-platelet agents (like clopidogrel or aspirin) unless treatment can safely be discontinued throughout duration of the study, by the discretion of the investigator. Occasional use is permitted. Prior treatment with any oligonucleotide or siRNA within 12 months prior to the first dosing day. Prior treatment with bepirovirsen."

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	21 Dec 2022	18
France	Not Recruiting	21 Dec 2022	30
Germany	Not Recruiting	21 Dec 2022	25
Greece	Not Recruiting	21 Dec 2022	8
Hungary	Not Recruiting	21 Dec 2022	14
Italy	Not Recruiting	21 Dec 2022	30
Poland	Not Recruiting	21 Dec 2022	30
Romania	Not Recruiting	21 Dec 2022	55
Spain	Not Recruiting	21 Dec 2022	25