Phase 2a Open-Label Study on Safety and Pharmacodynamics of Imdusiran and Durvalumab in Chronic Hepatitis B Patients
- Trial ID
- 2023-509573-23-00
- Protocol
- AB-729-203
- Sponsor
- Arbutus Biopharma Inc.
Trial statistics
Objectives
The primary objective of this Phase 2a, open-label study is to evaluate the **safety** and **tolerability** of **imdusiran** and **durvalumab** in subjects with **chronic HBV infection** who are suppressed on nucleos(t)ide analogues (NA). This is clinically relevant as it aims to ensure that the combination therapy is safe for patients, which is a critical step before considering efficacy and broader clinical application.
Secondary objectives include:
- Determining the effect of imdusiran and durvalumab on **HBsAg** and other viral markers, which could provide insights into the antiviral activity of the treatment.
- Characterizing the target engagement (TE) and pharmacodynamics (PD) of durvalumab in chronic HBV subjects over time, which is essential for understanding the drug's mechanism of action and optimizing dosing regimens.
- Determining the proportion of subjects who meet NA treatment discontinuation criteria, which could inform future guidelines on treatment cessation and management of chronic HBV infection.
Participants
The clinical trial involves a total of **17 participants** diagnosed with **Chronic HBV Infection**. The study population includes both male and female subjects, aged between 18 and 65 years. Participants are required to have a **Body Mass Index (BMI)** ranging from 18 to 38 kg/m². The selection criteria ensure that subjects are capable of providing informed consent and adhering to the study protocol. Participants must have documented chronic HBV infection, with specific serological markers present for at least six months prior to screening. The trial includes individuals who are either HBeAg-positive or HBeAg-negative, with HBsAg levels not exceeding 1,000 IU/mL at screening. A liver ultrasound confirming the absence of clinically significant abnormalities is mandatory within six months prior to the study's commencement. Additionally, all subjects must demonstrate a non-cirrhotic status through either a liver biopsy or a Fibroscan® result. The trial population was selected based on these criteria to ensure the safety and tolerability of the investigational treatments, imdusiran and durvalumab, in nucleos(t)ide analogue suppressed chronic hepatitis B subjects.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and tolerability of **Imdusiran** (AB-729) in combination with intermittent dosing of **Durvalumab** in subjects with **chronic HBV infection**. This is a Phase 2a, open-label, multiple-dose study. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, BMI, and documented chronic HBV infection. Participants will be required to have a liver ultrasound and fibrosis assessment to confirm non-cirrhotic status. The trial is expected to start recruitment on April 30, 2024, and conclude by July 31, 2027, with a maximum treatment period of 48 weeks.
Participants will be involved in the study for the duration of the treatment period, with follow-up visits scheduled to monitor the frequency and severity of treatment-emergent adverse events (TEAEs) and immune-related adverse events (irAEs). Vital signs, physical exams, and electrocardiogram (ECG) abnormalities will also be assessed. The study will be conducted in an open-label format, meaning both the researchers and participants will be aware of the treatment being administered. The trial will not be blinded or placebo-controlled.
The expected length of participant involvement is up to 48 weeks, with conditions for early termination including the occurrence of severe adverse events or non-compliance with study protocols. Participants will be required to adhere to contraceptive guidance throughout the study and for a specified period after discontinuation. The end-of-study visit will involve a final assessment of safety and tolerability, as well as the collection of any remaining data required for the study's primary endpoints.
Treatment
The clinical trial involves the administration of **Imdusiran**, a **solution for injection** developed by Arbutus Biopharma Corporation. The active substance in Imdusiran is AB-729, which is classified as a nucleic acid. The medication is administered via the **subcutaneous route**. The dosing regimen for Imdusiran includes a maximum daily dose of 60 mg, with a total maximum dose of 360 mg over a treatment period of 48 weeks. The pharmaceutical form is specifically designed for injection, ensuring precise delivery of the active compound. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.
In addition to Imdusiran, the trial also includes the administration of **IMFINZI**, a **concentrate for solution for infusion** produced by AstraZeneca AB. The active substance in IMFINZI is **Durvalumab**, a monoclonal antibody targeting PD-L1, classified as a protein of other origin. This medication is administered via **intravenous use**. The dosing schedule for Durvalumab allows for a maximum daily dose of 120 mg, with a total maximum dose of 240 mg over the same 48-week treatment period. The infusion form facilitates controlled administration and absorption of the biologic agent. Compliance with the infusion schedule is similarly monitored to ensure protocol adherence.
Both Imdusiran and IMFINZI are utilized as test products in this Phase 2a, open-label, multiple-dose study. The primary objective is to evaluate the safety and tolerability of these medications in subjects with chronic hepatitis B virus (HBV) infection who are nucleos(t)ide analogue (NA) suppressed. The study does not include any non-experimental treatments such as standard-of-care therapy or placebo. The trial design ensures that all participants receive the investigational treatments, allowing for a comprehensive assessment of their pharmacodynamics and safety profiles.
Efficacy
The efficacy of the clinical trial will be assessed through the evaluation of primary endpoints, which include the frequency and severity of treatment-emergent adverse events (TEAEs) and immune-related adverse events (irAEs), as well as discontinuations due to adverse events and irAEs. Additionally, the frequency and severity of laboratory abnormalities by cohort will be monitored, alongside vital signs, physical examination, and electrocardiogram (ECG) abnormalities. These parameters will be collected and analyzed to determine the safety and tolerability of the investigational products, **Imdusiran** and Durvalumab, in subjects with chronic hepatitis B virus (HBV) infection. The trial is designed as a Phase 2a, open-label, multiple-dose study, focusing on the pharmacodynamics of the combination therapy. The study will involve regular assessments at specified intervals throughout the treatment period, ensuring comprehensive data collection for efficacy evaluation.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject must be 18 (or other appropriate age of consent) to 65 years of age, inclusive, at the time of signing the informed consent.
- BMI ≥18 kg/m2 and ≤38 kg/m2
- Male or female a. Male subjects: A male subject is eligible to participate if he does not have a female partner who is pregnant or who intends to become pregnant during the study. A male subject must agree to use contraception as detailed in Appendix 3 starting 4 weeks prior to Day 1, during the Treatment Period, and throughout the Follow-Up Period. If a male subject discontinues the study early, they should continue to follow the contraceptive guidance for 3 months after the last dose of study treatment, and refrain from donating sperm during this period. Male subjects should also be advised of the benefit for their female partners (who are woman of childbearing potential [WOCBP]) to use a highly effective method of contraception as detailed in Appendix 3. b. Female subjects: A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: i. Not a WOCBP as defined in Appendix 3 OR ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 starting 4 weeks prior to Day 1, during the Treatment Period, and the Follow-Up Period. If a female subject discontinues the study early, they should continue to follow the contraceptive guidance for 3 months after the last dose of study treatment.
- Documented chronic HBV infection: a. Positive HBsAg, HBV DNA, or HBeAg at least 6 months prior to the Screening Visit (historical documentation must be provided) and negative serum IgM anti-hepatitis B core-related antibody (HBcAb) at the Screening Visit.
- Subjects may be HBeAg-positive or HBeAg negative.
- HBsAg ≤1,000 IU/mL at Screening.
- Subjects must have HBV DNA
- Liver ultrasound with absence of clinically significant abnormalities is required within 6 months prior to Day 1
- All subjects must have assessment of fibrosis demonstrating non-cirrhotic status available at Screening. Non-cirrhotic subjects are defined by: a. Liver biopsy demonstrating a Metavir Fibrosis Score of F0-2 (or equivalent) within 12 months prior to Day 1 (liver biopsy results supersede Fibroscan® results); OR b. Fibroscan® result of ≤8.5 kPa within 6 months prior to Day 1
- Capable of giving signed informed consent, able to understand and comply with protocol requirements, instructions, and protocol-related restrictions, and likely to complete the study as planned.
Exclusion Criteria
- Known co-infection with any of the following: a. HIV, b. HCV, c. Hepatitis D virus (HDV)
- Any known preexisting medical or psychiatric condition that could interfere with the subject’s ability to provide informed consent or participate in study conduct, or that may confound study findings including, but not limited to: a. History of any clinically significant medical condition associated with chronic liver disease that may affect the ability to respond to HBV therapy. b. Immunologically mediated disease. c. Significant immunosuppression from, but not limited to, organ transplantation, immunodeficiency conditions such as common variable hypogammaglobulinemia or receipt of systemic immunosuppressive medications during the study or ≤6 months prior to the first dose of study treatment, including but not limited to: azathioprine, methotrexate, cyclosporine, rituximab, other chemotherapy, biologics and/or prednisone or equivalent steroid (>10 mg/day for >2 weeks). d. History of thyroid disease (hyper- or hypothyroidism). e. f. Known chronic or severe infection or recent significant exposure to infections such as tuberculosis or endemic mycosis or untreated latent infections (i.e., latent tuberculosis). g. Current or history of interstitial lung disease or pneumonitis h. History of long-COVID or severe COVID-19 infection necessitating ICU admission and/or invasive ventilation. i. Current or history of any clinically significant cardiac abnormalities/dysfunction such as congestive heart failure, myocardial infarction ≤6 months prior to the Screening Visit, pulmonary hypertension, complex congenital heart disease, significant arrhythmia, and/or active cardiac ischemia. j. Current uncontrolled hypertension or past medical history of hypertensive crisis. k. History of cirrhosis at any time, or evidence of decompensated liver disease including, but not limited to, a history or presence of clinical ascites, bleeding esophageal varices, hepatorenal syndrome, liver transplantation and/or hepatic encephalopathy. l. Liver ultrasound or other imaging with findings suggestive of hepatocellular carcinoma at any time. m. Clinically unstable medical condition ≤2 weeks prior to the first dose of study treatment. n. Psychiatric condition(s), including but not limited to suicidal or homicidal ideation and/or attempt.
- Evidence of active or suspected malignancy, or a history of malignancy ≤3 years prior to the Screening Visit (except adequately treated carcinoma in situ and basal cell carcinoma of the skin). Subjects under evaluation for malignancy are not eligible.
- History or current use of ICI therapy or radiation therapy.
- History of anaphylactic or severe allergic reactions likely to be exacerbated by any component of imdusiran or durvalumab.
- Poor venous access that precludes the peripheral blood sampling required for this study.
- QTcF interval >450 msec for males or >470 msec for females.
- ALT >2× ULN of the laboratory reference range.
- Direct or total bilirubin >1.5 × ULN of the laboratory reference range.
- International normalized ratio (INR) >ULN of the laboratory reference range.
- Any of the following hematologic criteria (growth factors may not be used to achieve study entry requirements): a. Neutrophils <1500/mm3 (African descent: <1200/mm3); OR b. Platelets <110,000/mm3.
- Estimated creatinine clearance <60 mL/min, calculated using the CKD-EPI (2021) formula. The formula can be found at https://www.kidney.org/professionals/kdoqi/gfr_calculator/. Age, gender, and creatinine must be entered. Cystatin is to be left blank.
- Poorly controlled Type 2 diabetes mellitus with whole blood hemoglobin A1c (HbA1c) ≥8%.
- Abnormal thyroid stimulating hormone (TSH) or free thyroxine (T4) values out of the laboratory reference ranges.
- Abnormal adrenocorticotropic hormone (ACTH) and/or cortisol values out of the laboratory reference ranges.
- Alpha fetoprotein (AFP) >10 ng/mL.
- Positive or repeatedly indeterminate value for QuantiFERON test (indeterminate tests should be confirmed with a repeat QuantiFERON test) in subjects without a history of adequately treated active or latent tuberculosis.
- Clinical diagnosis of substance abuse with alcohol, narcotics, or cocaine ≤12 months prior to the Screening Visit, except for those subjects monitored in an opioid substitution maintenance program.
- Previous treatment with an experimental HBV-directed RNA-interference (including imdusiran) or antisense oligonucleotide product. History of any other prior experimental HBV treatment must be approved by the Sponsor Medical Monitor.
- Receipt of immunoglobulin or other blood products within 3 months prior to screening, or at any time during participation in the study.
- Receipt of any vaccines (live attenuated or inactivated vaccine) within 30 days prior to Screening Visit 1 or during the treatment period (until at least 6 weeks after the last dose of durvalumab).
- Participation in any investigational drug, vaccine, or device study within 3 months before study treatment administration, or within 90 days for a biologic therapy study or at any time during participation in the study.
- Prolonged therapy with biologics within 3 months before study treatment administration or at any time during participation in the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 30 Apr 2024 | 3 |
 Poland | Not Recruiting | 30 Apr 2024 | 4 |
 Romania | Not Recruiting | 30 Apr 2024 | 4 |
 Spain | Not Recruiting | 30 Apr 2024 | 2 |
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 |
|---|---|---|---|---|---|---|
Imdusiran | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 60 | 48 | PRD11045128 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 120 | 48 | PRD6651398 |