Evaluation of Tobevibart and Elebsiran Efficacy and Safety in Chronic Hepatitis D Virus Infection Unresponsive to Bulevirtide Therapy

The primary objective of this Phase 3 study is to evaluate the **antiviral efficacy** of the combination therapy of tobevibart and elebsiran in participants with Chronic Hepatitis D Virus (HDV) infection who have prior treatment experience with bulevirtide. This is clinically relevant as it aims to address the unmet need for effective antiviral treatments in this patient population, potentially improving virological suppression and clinical outcomes.

Secondary objectives include:

• Evaluating the long-term antiviral efficacy of tobevibart and elebsiran in participants with prior bulevirtide treatment experience.
• Assessing the effect of the combination therapy on alanine aminotransferase (ALT) levels and liver stiffness in these participants.
• Evaluating the safety profile of the combination therapy.
• Assessing the impact on end-stage liver disease outcomes.
• Evaluating the effect on hepatitis B surface antigen (HBsAg) levels.
• In Part II, evaluating the efficacy in maintaining sustained virological response (SVR) over time in participants who systematically interrupt treatment.
• Assessing the impact of treatment interruption on ALT levels and liver stiffness.
• Evaluating safety after treatment interruption and long-term safety in participants continuing therapy beyond Week 96.

The clinical trial involves a total of **18 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 criteria, including an HDV RNA level of at least 500 IU/mL at screening and a body mass index (BMI) ranging from 18 kg/m² to 40 kg/m². All participants have been receiving BLV treatment for a minimum of 24 weeks and are either noncirrhotic or have compensated cirrhotic liver disease. Additionally, they are on nucleoside reverse transcriptase inhibitor (NRTI) therapy against Hepatitis B Virus (HBV) for at least 12 weeks prior to the study or have HBV DNA levels below 20 IU/mL at screening. The trial includes individuals on specific NRTI therapies such as tenofovir alafenamide, tenofovir disoproxil fumarate, or entecavir. The study population is characterized by a vulnerable group, highlighting the importance of careful monitoring and ethical considerations throughout the trial.

The clinical trial is designed to evaluate the efficacy and safety of a combination therapy involving **tobevibart** and **elebsiran** in participants with **Chronic Hepatitis D Virus (HDV) Infection** who are not virologically suppressed with **bulevirtide**. This is a Phase 3, randomized, open-label study. The trial is structured into two parts, with the primary objective of Part I being to assess the antiviral efficacy of the combination therapy in participants with prior **bulevirtide** treatment experience. Part II aims to evaluate the efficacy of the combination therapy in achieving sustained virologic response (SVR) in participants who systematically interrupt treatment. The trial is expected to last until September 2031, with recruitment starting in June 2025.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, HDV RNA levels, and liver disease status. The inclusion criteria specify that participants must be adults aged 18 to 70 years, with HDV RNA levels of at least 500 IU/mL, and must have been receiving **bulevirtide** 2 mg subcutaneously daily for at least 24 weeks prior to Day 1. Follow-up visits will occur at regular intervals to monitor the primary and secondary endpoints, including HDV RNA levels, changes in liver function tests, and the incidence of adverse events. The primary endpoints for Part I include achieving HDV RNA levels below the lower limit of quantification (LLOQ) at Week 24, while Part II focuses on similar endpoints 24 weeks after the end of treatment.

The expected length of participant involvement is up to 240 weeks, depending on the part of the study they are enrolled in. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or the participant's decision to withdraw consent. The study will also monitor secondary endpoints such as changes in liver stiffness, incidence of decompensated cirrhosis, and progression to liver failure. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any remaining health concerns are addressed.

The clinical trial involves the administration of **VIR-3434**, an experimental medication formulated as a **lyophilized powder for solution for injection**. The active substance in VIR-3434 is **tobevibart**, a protein-based compound with high binding affinity to the neonatal Fc receptor. This medication is administered via **subcutaneous use**. The dosing schedule and frequency are determined by the study protocol, with a maximum treatment period of 240 days. Participant compliance is monitored throughout the trial to ensure adherence to the dosing regimen.

Another experimental medication used in the trial is **VIR-2218**, which is provided as a **solution for injection**. The active substance, **elebsiran**, is a nucleic acid-based compound designed to target the Hepatitis B virus. It contains several chemical modifications, including 2'-fluoro, 2’-O-methoxy, phosphorothioate backbone, and glycol nucleic acid modifications, and is conjugated to a triantennary N-acetylgalactosamine moiety. VIR-2218 is also administered via **subcutaneous injection**, with a treatment period extending up to 240 days. Compliance with the dosing schedule is closely monitored to ensure the integrity of the trial results.

The comparator treatment in this study is **HEPCLUDEX**, which contains the active substance **bulevirtide**. This medication is provided as a **powder for solution for injection** and is administered via **subcutaneous injection**. The maximum daily dose is 2 mg, with a total maximum dose of 336 mg over a treatment period of 24 days. HEPCLUDEX serves as a standard-of-care therapy for participants not virologically suppressed with bulevirtide, providing a benchmark for evaluating the efficacy of the experimental combination therapy. Compliance with the administration schedule is monitored to ensure accurate assessment of the treatment's efficacy and safety.

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 for Part I of the trial is the achievement of HDV RNA levels below the lower limit of quantification (LLOQ) and target not detected (TND) at Week 24. For Part II, the primary endpoint is the same HDV RNA measure 24 weeks after the end of treatment, at Week 120.

Secondary endpoints include additional timepoints for HDV RNA levels below LLOQ and TND at Weeks 48 and 96 for Part I, and at Weeks 144, 192, and 240 for Part II. Changes from baseline in HDV RNA and alanine aminotransferase (ALT) levels will be evaluated at multiple intervals, including Weeks 24, 48, 96, 120, 144, 192, and 240. The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) will be monitored through these timepoints as well.

Additional assessments include the incidence of decompensated cirrhosis, hepatocellular carcinoma (HCC), or progression to liver failure requiring transplantation or resulting in death. Changes in liver stiffness, as measured by liver elastography, and changes in hepatitis B surface antigen (HBsAg) levels will also be evaluated. These efficacy parameters will be collected and analyzed at specified intervals to determine the therapeutic impact of the combination therapy in the study population.