Evaluation of Efficacy and Safety of VIR-2218 (Elebsiran) and VIR-3434 (Tobevibart) in Chronic Hepatitis D Virus Infection
- Trial ID
- 2024-512203-40-00
- Protocol
- VIR-CHDV-V201
- Sponsor
- Vir Biotechnology Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of VIR-2218 and VIR-3434 in participants with **Chronic Hepatitis D Virus (HDV) Infection** in specific cohorts. This is clinically relevant as it aims to determine the potential of these investigational therapies to reduce viral load and improve patient outcomes in a condition with limited treatment options.
Secondary objectives include:
- Proportion of participants with undetectable HDV RNA or a significant decrease in HDV RNA from baseline, along with ALT normalization at various time points up to Week 192.
- Proportion of participants with undetectable HDV RNA at specified weeks.
- Proportion of participants with HDV RNA below the lower limit of quantitation at specified weeks.
- Change from baseline in HDV RNA at specified weeks.
- Proportion of participants with ALT normalization at specified weeks.
- Incidence and titers of anti-drug antibodies (ADA) to VIR-3434 at specified study visits.
- Change from baseline in liver fibrosis, MELD score, and CPT score at specified weeks.
Participants
The clinical trial involves a total of **35 participants** diagnosed with **Chronic Hepatitis D Virus (HDV) Infection**. The study population includes both male and female subjects, aged between 18 and 69 years. Participants were selected based on specific criteria, including a confirmed chronic HBV infection and a positive HDV antibody for at least six months prior to screening. All participants are required to be on locally approved NRTI therapy for a minimum of 12 weeks before the trial commencement. The trial population is characterized by a Body Mass Index (BMI) ranging from 18 kg/m² to 40 kg/m². Female participants must have a negative pregnancy test or be postmenopausal, and both male and female participants must adhere to strict contraceptive measures throughout the study duration and for 48 weeks following the last dose of the investigational drugs, VIR-2218 or VIR-3434. The trial also includes vulnerable populations, ensuring comprehensive informed consent is obtained from all participants.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy**, safety, and tolerability of two investigational therapies, VIR-2218 and VIR-3434, in participants with **chronic Hepatitis D virus infection**. This study is a Phase 2, randomized, double-blind, controlled trial. The trial is expected to last until March 2029, with recruitment having commenced in December 2022. Participants will be involved in the study for a maximum treatment period of 214 days, with the possibility of early termination if they experience significant adverse events or fail to comply with the study protocol.
The trial involves a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, body mass index, and laboratory-confirmed chronic Hepatitis B and D virus infections. Following the screening, eligible participants will be randomized to receive either VIR-2218 or VIR-3434 via subcutaneous injection. The primary endpoint is the proportion of participants achieving undetectable HDV RNA or a significant decrease in HDV RNA levels, along with normalization of alanine aminotransferase (ALT) at Week 24. Secondary endpoints include similar assessments at multiple time points up to Week 192, as well as changes in liver fibrosis and Model for End Stage Liver Disease (MELD) scores.
Participants will attend regular follow-up visits at specified intervals to monitor their response to treatment and any potential adverse events. These visits will include assessments of HDV RNA levels, ALT normalization, and other relevant clinical parameters. The end-of-study visit will occur after the final follow-up assessment, marking the conclusion of the participant's involvement in the trial. Conditions that may lead to early termination from the study include the occurrence of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) that compromise participant safety or the integrity of the study data.
Treatment
The clinical trial involves the administration of two experimental medications, **VIR-3434** and **VIR-2218**, to evaluate their efficacy, safety, and tolerability in participants with chronic Hepatitis D Virus infection. **VIR-3434** is a lyophilized powder for solution for injection, containing the active substance **tobevibart**, a human immunoglobulin G1 (IgG1) monoclonal antibody. This medication is administered via subcutaneous injection. The maximum daily dose is 300 mg, with a total maximum dose of 28,800 mg over a treatment period of 214 days. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.
**VIR-2218** is a solution for injection, containing the active substance **elebsiran**, a small interfering RNA (siRNA) targeting the Hepatitis B virus. This compound includes 2'-fluoro, 2’-O-methoxy modifications, phosphorothioate backbone modifications, glycol nucleic acid modification, and is conjugated to a triantennary N-acetylgalactosamine moiety. **VIR-2218** is also administered via subcutaneous injection. The maximum daily dose is 200 mg, with a total maximum dose of 9,600 mg over the same treatment period of 214 days. As with **VIR-3434**, the administration schedule and participant compliance are closely monitored to ensure proper dosing and adherence to the study protocol.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study. The trial is designed to assess the direct effects of the experimental medications on the target population. The study protocol includes detailed procedures for monitoring participant compliance and managing any treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) that may arise during the trial.
Efficacy
The efficacy of the investigational products VIR-2218 and VIR-3434 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 proportion of participants achieving undetectable HDV RNA levels, defined as below the limit of detection (LOD), or a reduction of at least 2 log10 in HDV RNA from baseline, coupled with the normalization of **alanine aminotransferase (ALT)** levels at Week 24. Secondary endpoints include similar assessments at multiple timepoints: Week 12, Week 48, Week 72, Week 96, Week 144, and Week 192. These endpoints will evaluate the proportion of participants with undetectable HDV RNA, a significant decrease in HDV RNA, and ALT normalization.
Additional secondary endpoints involve changes from baseline in HDV RNA levels, liver fibrosis, and scores on the Model for End Stage Liver Disease (MELD) and Child-Pugh-Turcotte (CPT) scales at specified intervals. The incidence and titers of anti-drug antibodies (ADA) to VIR-3434 will also be monitored up to Week 192 for relevant cohorts. Efficacy assessments will be conducted using validated laboratory tests and clinical evaluations at the designated timepoints throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 (or age of legal consent, whichever is older) to < 70 years at the time of screening Type of Participant and Disease Characteristics 2. Chronic HBV infection defined as a positive serum HBsAg, HBV DNA, or HBeAg on 2 occasions at least 6 months apart based on previous (within the past 12 months) or current laboratory documentation (any combination of these tests performed 6 months apart is acceptable) 3. On locally approved NRTI therapy for at least 12 weeks prior to Day 1 4. HBsAg > 0.05 IU/mL at screening 5. Positive HDV antibody for at least 6 months prior to screening and HDV RNA ≥ 500 IU/mL at screening 6. Serum alanine aminotransferase (ALT) > ULN and < 5 x ULN Weight 7. Body Mass Index (BMI) ≥ 18 kg/m2 to ≤ 40 kg/m2 Sex and Contraceptive/Barrier Requirements 8. Female participants must have a negative pregnancy test or confirmation of postmenopausal status. Postmenopausal status is defined as 12 months with no menses without an alternative medical cause (see Section 10.7 for additional details). Women of childbearing potential (WOCBP) must have a negative blood pregnancy test at screening and a negative urine pregnancy test on Day 1, cannot be breast feeding, and must be willing to use highly effective methods of contraception (Section 10.7) 14 days before study intervention administration through 48 weeks after the last dose of VIR-2218 or VIR-3434. Female participants must also agree to refrain from egg donation and in vitro fertilization from the time of study intervention administration through 24 weeks after the last dose of VIR-2218 or VIR-3434. 9. Male participants with female partners of childbearing potential must agree to meet 1 of the following contraception requirements from the time of study intervention administration through 24 weeks after the last dose of VIR-2218 or VIR-3434: documentation of vasectomy or azoospermia, or male condom use plus partner use of 1 of the contraceptive options listed for contraception for WOCBP (Section 10.7). Male participants must also agree to not donate sperm from the time of first study intervention administration through 24 weeks after the last dose of VIR-2218 or VIR-3434. Informed Consent 10. Capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol For the rest of the inclusion criteria, please refer to the study protocol.
Exclusion Criteria
- Medical Conditions 1. History of clinically significant liver disease from non-HBV and non- HDV etiology as determined by the investigator 2. History of clinically significant immune complex disease as determined by the investigator 3. History of clinically significant autoimmune disorder as determined by the investigator 4. History of HBV-related extrahepatic disease, including but not limited to HBV-related rash, arthritis, or glomerulonephritis 5. History of allergic reactions, hypersensitivity, or intolerance to study intervention, its metabolites or excipients 6. Anti-HBs >10 mIU/L at screening 7. Corrected QT interval (QTc) > 450 milliseconds 8. ALT or AST ≥ 5 x ULN 9. Total bilirubin > 2.0 mg/dL 10. Serum albumin < 30 g/L 11. Absolute neutrophil count < 1,000/mm3 (/μL) 12. International normalized ratio (INR) > 1.5 13. Hemoglobin < 8 g/dL 14. History of anaphylaxis 15. History of malignancy diagnosed or treated within 5 years (localized treatment of squamous or noninvasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to screening); participants under evaluation for malignancy are not eligible 16. History of or listed for bone marrow or solid organ transplant 17. Known active infection other than chronic HBV and HDV infection or any clinically significant acute condition such as fever (> 38° C) or acute respiratory illness within 7 days prior to Day 1 18. Coinfection with human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis C virus (HCV) or hepatitis E virus (HEV). Participants who are HCV antibody positive and HCV RNA negative are eligible. Participants who are HAV or HEV immunoglobulin M antibody (IgM) positive can be enrolled if asymptomatic and HAV or HEV immunoglobulin G antibody (IgG) positive. 19. Any clinically significant medical or psychiatric condition that may interfere with study intervention, assessment, or compliance with the protocol or otherwise makes the participant unsuitable for participation in the study, as determined by the investigator. Participants with controlled Diabetes Mellitus are eligible. 20. Acute or worsening chronic hepatitis, fluctuating or rapidly deteriorating hepatic function or use of any therapy known to exacerbate hepatic dysfunction in the opinion of the investigator. For the rest of the exclusion criteria, please refer to the study protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 05 Dec 2022 | 25 |
 France | Not Recruiting | 05 Dec 2022 | 35 |
 Germany | Not Recruiting | 05 Dec 2022 | 15 |
 Italy | Not Recruiting | 05 Dec 2022 | 10 |
 The Netherlands | Not Recruiting | 05 Dec 2022 | — |
 Romania | Not Recruiting | 05 Dec 2022 | 30 |
| Netherlands | — | — | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VIR-3434 | Test | LYOPHILIZED POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 300 | 214 | PRD10920517 |
VIR-2218 | Test | SOLUTON FOR INJECTION | SUBCUTANEOUS USE | 200 | 214 | PRD10920213 |