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

The primary objective of this Phase 3 multicenter, randomized, double-blind study is to evaluate the **treatment effect** of 24 weeks of bepirovirsen, including 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, which remains a significant global health challenge due to its chronic nature and potential for liver-related complications.

The clinical trial involves a total of **686 participants** diagnosed with **chronic Hepatitis B**. The study population includes both male and female subjects, with an age range that encompasses adults and older 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 excludes vulnerable populations. 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 selection criteria ensure that participants are willing and able to cease their NA treatment in accordance with the study protocol.

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 treated with nucleos(t)ide analogues. 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 or a placebo, both delivered as a solution for injection via subcutaneous use. The trial is expected to conclude by June 2026, with recruitment having commenced in January 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented chronic HBV infection for at least six months, stable nucleos(t)ide analogue therapy, and specific HBsAg and HBV DNA concentration thresholds. Following the screening, participants will be randomized to receive either bepirovirsen or placebo. The study includes regular follow-up visits to monitor safety, efficacy, and adherence to the treatment protocol. The primary endpoint is the achievement of a functional cure 24 weeks after discontinuation of all chronic HBV treatment, including bepirovirsen/placebo and nucleos(t)ide analogues, without the need for rescue medication.

The expected duration of participant involvement is approximately 24 weeks, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Bepirovirsen**, a **solution for injection** formulated for subcutaneous use. Bepirovirsen is a nucleic acid-based therapeutic agent developed by GlaxoSmithKline, identified by the sponsor product code GSK3228836B. The active substance, bepirovirsen, is administered at a dosage of 150 mg/mL. The maximum daily dose is 300 mg, with a total maximum dose of 7800 mg over a treatment period of 24 weeks. The dosing schedule includes loading doses to achieve a functional cure in participants with chronic Hepatitis B Virus (HBV) infection. Compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** control, which is a solution for injection designed to match the appearance and administration route of the active treatment. The placebo is administered subcutaneously at the same frequency and volume as the bepirovirsen solution, ensuring blinding of the study. The placebo is used to assess the efficacy and safety of bepirovirsen by providing a comparator for evaluating treatment outcomes. Participant compliance with the placebo administration is similarly monitored to maintain the integrity of the trial results.

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 HBeAg negative and have been treated with NA. The trial will involve a randomized, double-blind, multicenter approach to ensure the reliability and validity of the results. The primary endpoint will be measured at the end of the 24-week period after treatment cessation, providing a clear timeframe for assessing the sustained efficacy of the intervention.