Evaluation of Long-term Treatment Response Durability in Chronic Hepatitis B Patients Post-Bepirovirsen Therapy with or without Nucleos(t)ide Analogue Therapy

The primary objective of this study is to describe the **long-term durability** of treatment response in participants with **chronic hepatitis B** who have previously participated in a bepirovirsen treatment study. This objective is clinically relevant as it aims to evaluate the sustained efficacy of treatment, which is crucial for managing a chronic condition like hepatitis B, where long-term control of the virus can prevent liver damage and reduce the risk of liver cancer.

Secondary objectives include:

• Describing changes in disease after nucleos(t)ide analogue (NA) cessation in the B-Sure study, measured by time to HBsAg loss, time to virologic relapse, time to clinical relapse, and time to NA retreatment in participants who achieved a partial response in the parent study and discontinued NA treatment in B-Sure.
• Assessing long-term virology profiles by measuring the occurrence of anti-HBs, occurrence of anti-HBe, and changes from baseline over time in HBsAg, HBV DNA, HBeAg, HBcrAg, and HBV RNA in study participants.
• Evaluating the emergence of mutations within the bepirovirsen binding site and elsewhere in the hepatitis B genome when virological failure occurs in study participants.

The clinical trial involves a total of **344 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 represent adults. Participants were selected based on their previous involvement in studies where they received at least one dose of bepirovirsen, with specific criteria regarding their response to treatment and maintenance of certain health markers. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Participants are expected to have a stable health status, as they are required to cease their nucleos(t)ide analogue (NA) treatment according to a specified schedule. Lifestyle factors such as diet and physical activity are not explicitly detailed in the trial data provided.

The clinical trial is designed to evaluate the long-term durability of treatment response in participants with **Chronic Hepatitis B** who have previously participated in a bepirovirsen treatment study. This is a prospective, multi-centre, Phase 4 study, categorized as a non-low intervention trial. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from January 25, 2022, to March 24, 2029, with participant involvement expected to last until the end of the study period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as previous participation in a bepirovirsen study and the ability to cease nucleos(t)ide analogue (NA) treatment. Follow-up visits will be conducted to monitor the primary and secondary endpoints, including the time to virologic and clinical relapse, the occurrence of anti-HBs and anti-HBe antibodies, and changes in HBsAg, HBV DNA, and other relevant biomarkers. The end-of-study visit will conclude the participant's involvement, assessing the long-term treatment response durability.

The expected length of participant involvement is contingent upon maintaining eligibility criteria throughout the study. Conditions that may lead to early termination from the study include the inability to adhere to the NA cessation schedule or the occurrence of significant adverse events. The study will utilize a **solution for injection** containing the active substance bepirovirsen, administered via subcutaneous use. The trial aims to provide comprehensive data on the long-term effects of bepirovirsen in managing chronic hepatitis B, contributing valuable insights into the treatment's efficacy and safety profile.

The clinical trial involves the administration of the experimental medication **bepirovirsen**, which is a **nucleic acid**-based therapeutic agent. Bepirovirsen is provided in the pharmaceutical form of a **solution for injection**. The medication is administered via the **subcutaneous route**. The specific dosage and frequency of administration are not detailed in the provided data, but the maximum treatment period is indicated as one unit of time, with the unit unspecified. The product is identified by the sponsor product code GSK3228836B and is manufactured by GlaxoSmithKline. The medication is not formulated for pediatric use and is not classified as an orphan drug.

In addition to the experimental treatment, participants may be receiving standard-of-care therapy for **chronic hepatitis B**, which could include nucleos(t)ide analogs. The study aims to evaluate the long-term durability of treatment response in participants who have previously been treated with bepirovirsen. The trial does not specify the use of a placebo or comparator treatment. Participant compliance with the dosing schedule will be monitored, although specific methods for compliance monitoring are not detailed in the provided information.

Efficacy in this clinical trial will be assessed through several secondary endpoints related to the treatment of chronic hepatitis B. These endpoints include the time from nucleos(t)ide analogue (NA) cessation to the first occurrence of **virologic relapse**, the time to the first occurrence of clinical relapse, and the time to the first use of rescue medication. Additionally, the occurrence of anti-HBs (antibody to HBsAg) and anti-HBe (antibody to HBeAg) will be monitored. The study will also evaluate actual values and changes from Baseline at each study visit in HBsAg, HBV DNA, HBeAg, HBcrAg, and HBV RNA levels. Furthermore, the occurrence of mutations prior to bepirovirsen treatment in the parent study and at the time of virologic breakthrough will be assessed.