Study Investigating the Safety and Immunogenicity of AB-729 and VTP 300 in Virologically Suppressed CHB Participants
A Phase 2a, Randomized, Blinded, Multicenter Study Investigating a Combination of AB-729 and VTP-300 to evaluate their safety and reactogenicity in Virologically-Suppressed Chronic Hepatitis B Participants.
Arbutus Biopharma
62 participants
Jun 2, 2022
Interventional
Conditions
Summary
The study will assess the safety, antiviral activity, and immunogenicity of AB-729 followed by VTP-300 in virologically suppressed CHB participants. The study will enroll 62 stably NA-suppressed participants to receive AB-729 in addition to their NA for 24 weeks to lower HBsAg. Participants will then be randomized into one of two groups. Group A will receive active VTP-300 and Group B will receive VTP-300 placebo in addition to their NA. Participants will remain on their NA and be followed every 2-12 weeks for safety and efficacy assessments through Week 48. Group C an additional arm will assess if the addition of low dose nivolumab (0.3 mg/kg) to the MVA-HBV boost component of VTP-300 will further stimulate reduction of HBsAg after initial treatment with AB-729 followed by the ChAdOx1-HBV prime. If participants meet certain criteria (low ALT, low HBV-specific viral markers) at Week 48, they will stop their NA and be followed every 2-4 weeks for an additional 48 weeks to evaluate for functional cure. If participants do not meet these criteria they will stay on their NA and be followed every 12 weeks for 24 weeks. Participation will be for approximately 79-103 weeks, depending on whether NA discontinuation criteria are met. It is hoped that this study may lead to better understanding of host immune responses against HBV, and potentially facilitate immune control of HBV (functional cure).
Eligibility
Inclusion Criteria7
- Adult male or female participants, 18 to 65 years of age, inclusive.
- Male and female participants are eligible if they agree to use protocol-defined contraception
- Body mass index (BMI) greater than 18 kg/m2 and less than 35 kg/m2.
- Documented chronic HBV infection: positive HBsAg, HBV DNA, or HBeAg at least 6 months prior to the Screening Visit (historical documentation must be provided) and negative serum immunoglobulin M (IgM) anti-hepatitis B core-related antibody (HBcAb) at the Screening Visit
- Participants must have HBV DNA less than 20 IU/mL at screening and have been receiving either TAF, TDF, or ETV consistently for greater than 12 months prior to Day 1 and are willing to continue with the same NA treatment through the final study visit..
- HBsAg greater than 100 IU/ml and less than 5,000 IU/mL at Screening.
- All participants must have assessment of fibrosis demonstrating non-cirrhotic status.
Exclusion Criteria7
- Known co-infection with HIV, hepatitis A, C, D, or E
- Any known preexisting medical or psychiatric condition that could interfere with the participant’s ability to provide informed consent or participate in study conduct, or that may confound study findings
- History of any clinically significant medical condition associated with chronic liver disease, evidence of decompensated liver disease, findings suggestive of hepatocellular carcinoma (HCC) at any time. or cirrhosis at any time
- Immunologically mediated disease or significant immunosuppression from disease or medication.
- Any known or suspected hypersensitivity, anaphylactic reactions or previous severe reactions to any of the constituents of AB-729 or VTP-300.
- ALT greater than 2 × ULN of the laboratory reference range.
- Direct or total bilirubin greater than 1.5 × ULN of the laboratory reference range.
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Interventions
AB-729 is a GalNAc-conjugated siRNA inhibitor of hepatitis B virus (HBV). VTP-300 is an HBV-specific therapeutic vaccine that uses a prime-boost platform of ChAdOx1-HBV followed by MVA-HBV. Forty participants who are stably virally suppressed on oral tablet nucleos(t)ide analogue (NA) therapy [Tenofovir Disoproxil (TDF), Tenofovir Alafenamide (TAF) or Entecavir (ETV) will receive 60 mg of AB-729 subcutaneously every 8 weeks (Q8W) for the first 24 weeks plus NA daily. At Week 24 participants will be randomized 1:1 to one of 2 groups (Group A or B) to receive VTP-300 (intramuscular [IM] administration ChAdOx1-HBV (2.5 x 10¹°vp) at Week 26, followed by one dose of IM MVA-HBV [1 x 10 (power 8) pfu] at Week 30 or placebo plus NA. Randomization into Group A or Group B will be stratified by HBsAg level. Participants who experience a pre-determined decline in HBsAg from Week 26 to Week 34 will receive a second dose of IM MVA-HBV at Week 38. Participants, investigators and site staff performing safety assessments are blinded to the VTP-300. AB-729 and VTP-300 will be administered in the clinic only. Adherence will be monitored via clinical site staff recording and reporting administration of IP (AB-729 and VTP-300) and by subject dosing diary and tablet reconciliation at the site (NAs). At Week 48, all participants will be evaluated for eligibility to discontinue NA therapy based on levels of ALT, HBV DNA, HBeAg and HBsAg. Otherwise they will remain on their NA therapy. Participants who discontinue their NA will be followed for an additional 48 weeks. Participants who do not discontinue their NA will be followed for an additional 24 weeks After the first 40 participants have been allocated to Groups A or B, screening may proceed for Group C with aim to enrol 20 participants. Group C will be open label where all enrolled participants will receive AB-729 60 mg every 8 weeks + NA for 24 weeks and then receive a course of VTP-300 + nivolumab (ChAdOx1-HBV at Week 26, MVA-HBV + nivolumab (0.3 mg/kg via intravenous infusion) at Week 30. If a participant’s HBsAg at Week 34 is greater than or equal to 10IU/mL, the participant will receive a second dose, if eligible, of MVA-HBV + nivolumab at Week 38. Participants will remain on their NA therapy throughout the VTP-300administration period through Week 48. At Week 48 all participants will be evaluated for eligibility to either discontinue or remain on their NA treatment. Participants who discontinue their NA will be followed for an additional 48 weeks to monitor for safety and evidence of clinical or virologic relapse. Participants who do not discontinue their NA will be followed for an additional 24 weeks. This additional arm (Group C) was included that will assess if the addition of low dose nivolumab (0.3 mg/kg, one tenth the dose approved for oncologic indications) to the MVA-HBV boost component of VTP-300 will further stimulate reduction of HBsAg after initial treatment with AB-729 followed by the ChAdOx1-HBV prime.
Locations(3)
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ACTRN12622000317796