Efficacy and Safety Evaluation of Tobevibart and Elebsiran Combination Therapy Versus Bulevirtide in Chronic Hepatitis D Virus Infection

The primary objectives of this study are to evaluate the **antiviral efficacy** of the combination therapy of tobevibart and elebsiran compared to bulevirtide (BLV) in participants with chronic Hepatitis D Virus (HDV) infection, to assess the efficacy of tobevibart and elebsiran in achieving sustained virologic response (SVR) in participants who systematically interrupt treatment per protocol, and to evaluate the safety of tobevibart, elebsiran, and BLV in this patient population. These objectives are clinically relevant as they aim to determine the effectiveness and safety of a novel therapeutic approach for managing chronic HDV infection, which is a significant global health concern due to its association with severe liver disease.

The secondary objectives include:

• Evaluating the antiviral efficacy of tobevibart and elebsiran versus BLV in participants with chronic HDV infection.
• Assessing the impact of tobevibart and elebsiran versus BLV on alanine aminotransferase (ALT) levels, liver stiffness, and end-stage liver disease outcomes in participants with chronic HDV infection.
• Evaluating the effect of tobevibart and elebsiran versus BLV on HBsAg levels in participants with chronic HDV infection.
• Assessing the long-term antiviral efficacy and safety of tobevibart and elebsiran, including the maintenance of SVR over time in participants who systematically interrupt treatment per protocol.
• Evaluating the long-term impact of tobevibart and elebsiran on ALT and liver stiffness, as well as end-stage liver disease outcomes after long-term treatment and systematic treatment interruption per protocol.
• Assessing the antiviral effect on serum HBsAg after long-term treatment and systematic treatment interruption per protocol.
• Evaluating the long-term safety of tobevibart and elebsiran in participants with chronic HDV infection and assessing safety after systematic treatment interruption per protocol.

The clinical trial involves a total of **47 participants** diagnosed with **Chronic Hepatitis D Virus (HDV) Infection**. The study population comprises adult men and women aged between 18 and 70 years, inclusive. Participants were selected based on their positive HDV antibody or HDV RNA PCR results for at least six months prior to screening, with HDV RNA levels of at least 500 IU/mL at screening. The trial includes individuals with noncirrhotic or compensated cirrhotic liver disease and a body mass index (BMI) ranging from 18 kg/m² to 40 kg/m². All participants are required to be on nucleos(t)ide reverse transcriptase inhibitor (NRTI) therapy against Hepatitis B Virus (HBV) for at least 12 weeks prior to the start of the trial or have HBV DNA levels below 20 IU/mL at screening, continuing on locally approved NRTI therapy. The trial includes both male and female subjects and considers vulnerable populations. Participants' lifestyle factors such as diet, physical activity, and habits were not specified in the available data.

The clinical trial is a **Phase 2b** randomized, open-label study designed to evaluate the efficacy and safety of a combination therapy of **tobevibart** and **elebsiran** compared to **bulevirtide** in participants with **chronic Hepatitis D Virus (HDV) infection**. The trial aims to assess the antiviral efficacy, sustained virologic response, and safety profile of the investigational therapies. The study is structured to include multiple phases, with a primary focus on achieving HDV RNA levels below the lower limit of quantification and ensuring target not detected status at specified time points, such as Week 48 and Week 120. The trial is expected to span several years, with an estimated end date in December 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, and liver disease status. Following successful screening, participants will be randomized to receive either the combination therapy or bulevirtide. Regular follow-up visits will be conducted to monitor efficacy and safety endpoints, including changes in HDV RNA, liver function tests, and incidence of adverse events. The end-of-study visit will occur at the conclusion of the treatment period, with additional follow-up to assess long-term outcomes.

The expected length of participant involvement is up to 240 weeks, depending on the treatment arm and response to therapy. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial's design and procedures are meticulously crafted to ensure the collection of robust data while prioritizing participant safety and adherence to ethical standards.

The clinical trial involves the administration of **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 dosage is set at 2 mg per day, with a maximum total dose of 672 mg over a treatment period of 48 weeks. Bulevirtide is a protein-based therapeutic agent, specifically categorized under the ATC code J05AX28. The product is manufactured by Gilead Sciences Ireland Unlimited Company and is authorized for use in the European Union.

Another investigational product in the trial is **VIR-2218**, which contains the active substance **elebsiran**. This is a **solution for injection** administered through **subcutaneous use**. Elebsiran is a nucleic acid-based therapeutic, specifically an siRNA targeting the Hepatitis B virus. It includes modifications such as 2'-fluoro, 2’-O-methoxy, phosphorothioate backbone, and glycol nucleic acid, conjugated to a triantennary N-acetylgalactosamine moiety. The product is developed by Vir Biotechnology, Inc., and is designated as an orphan drug. The maximum treatment period for VIR-2218 is 240 weeks.

The trial also includes **VIR-3434**, which contains the active substance **tobevibart**. This medication is provided as a **lyophilized powder for solution for injection** and is administered via **subcutaneous use**. Tobevibart is a protein-based therapeutic, specifically an anti-HBsAg IgG1 LS monoclonal antibody with high binding affinity to the neonatal Fc receptor. Like VIR-2218, VIR-3434 is developed by Vir Biotechnology, Inc., and is designated as an orphan drug. The maximum treatment period for VIR-3434 is also 240 weeks.

Throughout the trial, participant compliance with the dosing schedule will be monitored to ensure adherence to the treatment protocol. The study aims to evaluate the antiviral efficacy and safety of the combination therapy of tobevibart and elebsiran compared to bulevirtide in participants with chronic Hepatitis D virus infection.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of **HDV RNA** levels, specifically achieving levels below the Lower Limit of Quantification (LLOQ) with Target Not Detected (TND) at Week 48 for Part 1, and at Week 120 for Part 2 following treatment interruption. Additionally, the incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) will be monitored through Week 48 as part of the primary safety assessment.

Secondary endpoints will further evaluate efficacy by measuring changes from baseline in **HDV RNA** and **ALT** levels at various timepoints, including Week 48, Week 96, and up to Week 240. Liver stiffness will be assessed using liver elastography, and the incidence of decompensated cirrhosis and hepatocellular carcinoma (HCC) will be recorded. The study will also track changes in **HBsAg** levels and provide categorical summaries at specified intervals. The incidence of TEAEs, SAEs, and laboratory abnormalities will be documented throughout the study duration, particularly from Week 96 to Week 240, to ensure comprehensive safety monitoring.