Efficacy and Safety Evaluation of Tobevibart and Elebsiran in Patients with Chronic Hepatitis D Virus Infection

The primary objective of this study is to evaluate the **efficacy** and **safety** of the combination therapy of tobevibart and elebsiran compared with delayed treatment in participants with **chronic Hepatitis D Virus (HDV) infection**. This is clinically relevant as chronic HDV infection is associated with severe liver disease, and effective treatment options are limited. Assessing the efficacy and safety of this combination therapy could provide a significant advancement in the management of this condition.

Secondary objectives include:

• Evaluating the antiviral effect of tobevibart and elebsiran on HDV viremia compared with delayed treatment.
• Assessing the impact on alanine aminotransferase (ALT) levels compared with delayed treatment.
• Determining the long-term efficacy and antiviral effect on HDV viremia.
• Evaluating the long-term impact on ALT levels and liver stiffness.
• Assessing the impact on end-stage liver disease outcomes.
• Evaluating the overall safety of the combination therapy in participants with chronic HDV infection.

The clinical trial involves a total of **109 participants** diagnosed with **Chronic Hepatitis D Virus (HDV) Infection**. The study population comprises adult men and women aged between 18 and 70 years, ensuring a diverse representation of both genders. Participants were selected based on specific health criteria, including a positive HDV antibody or RNA PCR result for at least six months prior to screening, and a serum alanine aminotransferase (ALT) level greater than the upper limit of normal but less than five times the upper limit. The trial includes individuals with noncirrhotic or compensated cirrhotic liver disease and a body mass index (BMI) ranging from 18 to 40 kg/m². Participants are required to be on nucleos(t)ide reverse transcriptase inhibitor (NRTI) therapy against HBV for at least 12 weeks prior to the trial or have HBV DNA levels below 20 IU/ml at screening. The study does not involve a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is a **Phase 3** randomized, open-label study designed to evaluate the efficacy and safety of a combination therapy involving **tobevibart** and **elebsiran** in participants with **chronic Hepatitis D Virus (HDV) infection**. The trial aims to compare the combination therapy with delayed treatment, assessing both efficacy and safety outcomes. The study is structured to include two arms, with primary endpoints focusing on achieving HDV RNA levels below the lower limit of quantification (LLOQ), target not detected (TND), and normalization of alanine aminotransferase (ALT) levels at specific time points. The trial is expected to span a total duration of approximately 240 weeks, with an estimated recruitment start date in June 2025 and an anticipated end date in February 2031.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, HDV RNA levels, liver disease status, and current treatment regimens. Following the screening, participants will be randomized into one of the study arms. Regular follow-up visits will be conducted to monitor the primary and secondary endpoints, including HDV RNA levels, ALT levels, and safety assessments through the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). The end-of-study visit will conclude the participant's involvement, with comprehensive evaluations to assess the long-term effects of the treatment.

The expected length of participant involvement is up to 240 weeks, contingent upon adherence to the study protocol and absence of conditions warranting early termination. Early termination may occur due to significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is not categorized as low intervention, given its therapeutic confirmatory nature involving drugs not currently authorized for the population under study. The study's design and methodology are aligned with regulatory standards to ensure the collection of robust and reliable data on the investigational therapy's efficacy and safety profile.

The clinical trial involves the administration of two experimental medications, **VIR-2218** and **VIR-3434**, both developed by VIR Biotechnology, Inc. **VIR-2218** is a solution for injection containing the active substance **elebsiran**, a nucleic acid-based compound. It is designed as a small interfering RNA (siRNA) targeting the Hepatitis B virus, featuring 2'-fluoro, 2’-O-methoxy modifications, phosphorothioate backbone modifications, glycol nucleic acid modification, and is conjugated to a triantennary N-acetylgalactosamine moiety. The medication is administered via subcutaneous injection. The maximum daily dose is 1 mg, and the treatment period extends up to 240 days.

**VIR-3434** is provided as a lyophilized powder for solution for injection, containing the active substance **tobevibart**, a protein-based compound. It is an anti-HBsAg IgG1 LS monoclonal antibody with high binding affinity to the neonatal Fc receptor. This medication is also administered subcutaneously. Similar to VIR-2218, the maximum daily dose is 1 mg, with a treatment duration of up to 240 days.

Both medications are classified as orphan drugs and are not formulated for pediatric use. The trial aims to evaluate the efficacy and safety of the combination therapy of tobevibart and elebsiran in participants with chronic Hepatitis D virus (HDV) infection. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data. Participant compliance with the dosing schedule will be monitored throughout the study period.

The efficacy of the combination therapy of **tobevibart** and **elebsiran** in participants with chronic Hepatitis D Virus (HDV) infection will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the achievement of HDV RNA levels below the lower limit of quantification (LLOQ), with the target not detected (TND), and normalization of alanine aminotransferase (ALT) levels (ALT ≤ upper limit of normal, ULN) at Week 48 for Arm 1 compared to Week 12 for Arm 2. Secondary efficacy endpoints include HDV RNA < LLOQ, TND at Week 48 for Arm 1 versus Week 12 for Arm 2, and changes from baseline in HDV RNA and ALT levels at specified time points.

Measurements will be conducted at multiple time points, including Weeks 48, 96, 144, 192, and 240, to evaluate the long-term efficacy of the treatment. The assessment will involve laboratory tests to quantify HDV RNA levels and measure ALT levels, ensuring that these parameters are within the defined limits. Additionally, liver stiffness will be evaluated using liver elastography, and the incidence of decompensated cirrhosis, hepatocellular carcinoma (HCC), and progression to liver failure will be monitored throughout the study duration. The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) will also be recorded as part of the safety assessment.