Open-Label Study of Imdusiran (AB-729) in Combination with Intermittent Dosing of Durvalumab in Subjects with Chronic HBV Infection

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Arbutus Biopharma Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

16 Jul 2024 → 2 Aug 2024

Decision date (initial)

2024-06-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Arbutus Biopharma Corporation

External identifiers

EU CT number

2023-509573-23-00

ClinicalTrials.gov

NCT06245291

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Others, Safety

To evaluate the safety and tolerability of imdusiran and durvalumab in NA suppressed CHB subjects

Secondary objectives 3

1. To determine the effect of imdusiran and durvalumab on HBsAg and other viral markers
2. To characterize the target engagement (TE) (pharmacodynamics [PD]) of durvalumab in CHB subjects over time
3. To determine the proportion of subjects who meet NA treatment discontinuation criteria

Conditions and MedDRA coding

Chronic HBV Infection

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Subject must be 18 (or other appropriate age of consent) to 65 years of age, inclusive, at the time of signing the informed consent.
2. BMI ≥18 kg/m2 and ≤38 kg/m2
3. 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.
4. 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.
5. Subjects may be HBeAg-positive or HBeAg negative.
6. HBsAg ≤1,000 IU/mL at Screening.
7. Subjects must have HBV DNA
8. Liver ultrasound with absence of clinically significant abnormalities is required within 6 months prior to Day 1
9. 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
10. 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 23

1. Known co-infection with any of the following: a. HIV, b. HCV, c. Hepatitis D virus (HDV)
2. 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.
3. 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.
4. History or current use of ICI therapy or radiation therapy.
5. History of anaphylactic or severe allergic reactions likely to be exacerbated by any component of imdusiran or durvalumab.
6. Poor venous access that precludes the peripheral blood sampling required for this study.
7. QTcF interval >450 msec for males or >470 msec for females.
8. ALT >2× ULN of the laboratory reference range.
9. Direct or total bilirubin >1.5 × ULN of the laboratory reference range.
10. International normalized ratio (INR) >ULN of the laboratory reference range.
11. 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.
12. 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.
13. Poorly controlled Type 2 diabetes mellitus with whole blood hemoglobin A1c (HbA1c) ≥8%.
14. Abnormal thyroid stimulating hormone (TSH) or free thyroxine (T4) values out of the laboratory reference ranges.
15. Abnormal adrenocorticotropic hormone (ACTH) and/or cortisol values out of the laboratory reference ranges.
16. Alpha fetoprotein (AFP) >10 ng/mL.
17. 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.
18. 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.
19. 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.
20. Receipt of immunoglobulin or other blood products within 3 months prior to screening, or at any time during participation in the study.
21. 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).
22. 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.
23. Prolonged therapy with biologics within 3 months before study treatment administration or at any time during participation in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. The frequency and severity of treatment emergent adverse events (TEAEs) and irAEs, and discontinuations due to AEs and irAEs
2. The frequency and severity of laboratory abnormalities by cohort
3. Vital signs, physical exam and electrocardiogram (ECG) abnormalities

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Arbutus Biopharma Inc.

Sponsor organisation

Arbutus Biopharma Inc.

Address

701 Veterans Circle

City

Warminster

Postcode

18974-3531

Country

United States

Scientific contact point

Organisation

Arbutus Biopharma Inc.

Contact name

Lester Gibbs

Public contact point

Organisation

Arbutus Biopharma Inc.

Contact name

Lester Gibbs

Third parties 14

Locations

4 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

2 submissions — initial application plus substantial / non-substantial modifications