A Study Evaluating Treatment Regimens Containing Vebicorvir (ABI-H0731) in Participants With Chronic Hepatitis B Infection

A Randomized Phase 2a, Multicenter, Open-Label, Multiple-Cohort Study Evaluating Regimens Containing Vebicorvir in Subjects With Chronic Hepatitis B Virus Infection

The purpose of this study is to determine if vebicorvir (VBR, ABI-H0731) in combination with AB-729 is safe and effective in participants with chronic hepatitis B infection (cHBV) receiving a standard of care nucleos(t)ide/reverse transcriptase inhibitor (SOC NrtI).

Study Overview

• Status: Terminated
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: VBR; Drug: AB-729; Drug: SOC NrtI

Detailed Description

The initial cohort of participants will be enrolled in 3 treatment groups receiving 1) VBR + AB-729 + SOC NrtI, 2) VBR + SOC NrtI, or 3) AB-729 + SOC NrtI for up to 48 weeks. At Week 48, all participants will have an assessment of Treatment Stopping Criteria. Any participant who meets the Treatment Stopping Criteria, will discontinue their assigned treatment including NrtI and will remain in follow-up through Week 96. The participants who do not meet the Treatment Stopping Criteria will continue treatment with NrtI alone and will remain in follow-up through Week 96. Up to an additional 2 cohorts may be added to the study in future protocol amendments.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Saint Vincent's Hospital Sydney
    • Kogarah, New South Wales, Australia, 2217
      • Saint George Hospital - Australia
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Victoria
    • Footscray, Victoria, Australia, 3011
      • Footscray Hospital
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
    • Parkville, Victoria, Australia, 3050
      • Melbourne Health
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Bulgaria
  • Sofia, Bulgaria, 1407
    • Acibadem City Clinic Tokuda Hospital
  • Sofia, Bulgaria, 1431
    • University Multiprofile Hospital for Active Treatment St. Ivan Rilski
  • Stara Zagora, Bulgaria, 6000
    • Nov Rehabilitatsionen Tsentar EOOD
  • Sofia City
    • Sofia, Sofia City, Bulgaria, 1431
      • Diagnostic Consultative Center Aleksandrovska
• Canada
  • Québec, Canada, G1V 4G2
    • Centre Hospitalier Université de Québec - Université Laval
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2K5
      • Pacific Gastroenterology Associates
    • Vancouver, British Columbia, Canada, V6Z 2C7
      • Vancouver Infectious Disease Centre
  • Ontario
    • London, Ontario, Canada, N6A 2C2
      • University Hospital - London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Research Institute
    • Toronto, Ontario, Canada, M6H 3M1
      • Toronto Liver Centre
• New Zealand
  • Auckland, New Zealand, 1010
    • Auckland Clinical Studies
  • Wellington, New Zealand, 6021
    • Wellington Regional Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Body mass index (BMI) 18 to 36 kg/m^2 and a minimum body weight of 45 kg (inclusive)
• Female participants must be non-pregnant and have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Day 1
• Chronic Hepatitis B defined as HBV infection documented for ≥6 months prior to Screening
• Hepatitis B 'e' antigen (HBeAg) negative at least 3 months prior to Screening Visit (historical documentation) AND at the Screening Visit
• Virologically suppressed on SOC NrtI therapy with nonquantifiable HBV DNA for at least 6 months prior to Screening
• On a stable SOC NrtI regimen of ETV, TDF, or TAF for >12 months
• HBsAg ≥100 international units/mL at Screening
• Lack of bridging fibrosis or cirrhosis
• Agreement to comply with protocol-specified contraceptive requirements
• In good general health, except for cHBV, in the opinion of the Investigator
• Able to take oral medication and willing to receive subcutaneous injections of AB-729.

Exclusion Criteria:

• Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis D virus (HDV), acute hepatitis A virus (HAV), or acute hepatitis E virus (HEV)
• Females who are lactating or wish to become pregnant during the course of the study
• History of liver transplant or evidence of advanced liver disease, cirrhosis, or hepatic decompensation at any time prior to, or at the time of Screening
• History of persistent alcohol abuse or illicit drug abuse within 3 years prior to Screening
• Clinically significant diseases or conditions, such as cardiac disease, including poorly-controlled or unstable hypertension; pulmonary disease; chronic or recurrent renal or urinary tract disease; liver disease other than cHBV; endocrine disorder; autoimmune disorder; poorly controlled diabetes mellitus; neuromuscular, musculoskeletal, or mucocutaneous conditions requiring frequent treatment, seizure disorders requiring treatment; ongoing infection or other medical conditions requiring frequent medical management or pharmacologic or surgical treatment that, in the opinion of the Investigator or the Sponsor, makes the subject unsuitable for study participation
• History of hepatocellular carcinoma (HCC)
• History of malignancy other than HCC unless the subject's malignancy has been in complete remission off chemotherapy and without additional medical or surgical interventions during the 3 years before Screening
• History or presence at Screening of electrocardiogram (ECG) abnormalities deemed clinically significant, in the opinion of the Investigator
• History of hypersensitivity or idiosyncratic reaction to any components or excipients of the investigational drugs
• History of any significant food or drug-related allergic reactions such as anaphylaxis or Stevens-Johnson syndrome

• Exclusionary laboratory results at Screening:

  1. Platelet count <100,000/mm^3
  2. Albumin <3 g/dL
  3. Direct bilirubin >1.2× upper limit of normal (ULN)
  4. ALT ≥5× ULN
  5. Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is > ULN but <100 ng/mL, the subject is eligible if hepatic imaging prior to initiation of study drug reveals no lesions indicative of possible HCC
  6. International Normalized Ratio (INR) >1.5× ULN
  7. Estimated creatinine clearance (CrCl) <50 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight at Screening
  8. Any other laboratory abnormality deemed clinically significant by the Investigator
• Current or prior use of prohibited (per protocol) concomitant medications from 28 days prior to Day 1.

• Current or prior treatment for cHBV with:

  • Lamivudine, telbivudine or adefovir (any duration)
  • HBV core inhibitor (any duration)
  • siRNA or other oligonucleotide therapeutic (any duration)
  • Interferon in the 6 months prior to Screening
  • Any investigational agent for cHBV in the 6 months prior to Screening.
• Participation in another clinical study of a drug or device whereby the last investigational drug/device administration is within 60 days or 5 half-lives prior to study start.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VBR + AB-729 + SOC NrtI; Participants with cHBV received VBR + AB-729 + SOC NrtI for 48 weeks followed by 48 weeks in follow-up.	Drug: VBR; VBR is an HBV core protein inhibitor. Participants will receive VBR 300 mg tablets orally once daily (QD).; Other Names: Vebicorvir, ABI-H0731; Drug: AB-729; AB-729 is a small interfering ribonucleic acid (siRNA) inhibitor of HBV. Participants will receive a 60-mg subcutaneous injection of AB-729 once every 8 weeks.; Drug: SOC NrtI; Participants will receive their SOC NrtI (ETV, TDF or TAF) tablet orally as per approved package insert.; Other Names: Tenofovir disoproxil fumarate (TDF); Entecavir (ETV); Tenofovir alafenamide (TAF)
Other: VBR + SOC NrtI; Participants with cHBV received VBR + SOC NrtI for 48 weeks followed by 48 weeks in follow-up. This treatment was used as a reference regimen.	Drug: VBR; VBR is an HBV core protein inhibitor. Participants will receive VBR 300 mg tablets orally once daily (QD).; Other Names: Vebicorvir, ABI-H0731; Drug: SOC NrtI; Participants will receive their SOC NrtI (ETV, TDF or TAF) tablet orally as per approved package insert.; Other Names: Tenofovir disoproxil fumarate (TDF); Entecavir (ETV); Tenofovir alafenamide (TAF)
Other: AB-729 + SOC NrtI; Participants with cHBV received AB-729 + SOC NrtI for 48 weeks followed by 48 weeks in follow-up. This treatment was used as a reference regimen.	Drug: AB-729; AB-729 is a small interfering ribonucleic acid (siRNA) inhibitor of HBV. Participants will receive a 60-mg subcutaneous injection of AB-729 once every 8 weeks.; Drug: SOC NrtI; Participants will receive their SOC NrtI (ETV, TDF or TAF) tablet orally as per approved package insert.; Other Names: Tenofovir disoproxil fumarate (TDF); Entecavir (ETV); Tenofovir alafenamide (TAF)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With One or More Adverse Events (AEs)	AEs were collected from the time of signing the informed consent until the final follow-up visit, up to 96 weeks.
Number of Participants With Premature Treatment Discontinuation Due to AEs	AEs were collected from the time of signing the informed consent until the final follow-up visit, up to 96 weeks.
Number of Participants With One or More Abnormal Laboratory Result	Laboratory results were collected from the time of signing the informed consent until the study was early terminated, up to 96 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Levels of VBR		Before dosing at Baseline (Day 1) and at pre-specified time points up to 48 weeks, and at Week 52
Plasma Levels of AB-729		2 hours after dosing at pre-specified time points up to 40 weeks
Plasma Levels of SOC NrtI (ETV, TDF, TAF)		Before dosing at Baseline (Day 1) and at pre-specified time points up to 48 weeks
Change From Baseline in Mean log10 Serum Hepatitis B Surface Antigen (HBsAg) On-Treatment	Subjects remained on their assigned oral agents (ie, VBR+NrtI for Groups 1 and 2; NrtI for Group 3) until Week 48 laboratory results required for Treatment Stopping Criteria assessment were available so there are some results past Week 48.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56.
Number of Participants With Serum HBsAg Below the Lower Limit of Quantitation (<LLOQ)		Pre-specified time points up to 96 weeks
Number of Participants With HBV Deoxyribonucleic Acid (DNA) Not Detected (<5 IU/mL)		Week 48
Number of Participants With HBV Ribonucleic Acid (RNA) <LLOQ		Week 48
Change From Baseline in Mean log10 HBV RNA On-Treatment	Subjects remained on their assigned oral agents (ie, VBR+NrtI for Groups 1 and 2; NrtI for Group 3) until Week 48 laboratory results required for Treatment Stopping Criteria assessment were available so there are some results past Week 48.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56.
Change From Baseline in Mean log10 Hepatitis B Core-related Antigen (HBcrAg) On-Treatment		Baseline and Week 48
Number of Participants With HBsAg Seroconversion		Week 48
Number of Participants With Normal Alanine Aminotransferase (ALT)		Baseline and at pre-specified time points up to 96 weeks
Change From Baseline in Mean log10 Serum Hepatitis B Surface Antigen (HBsAg) Off-Treatment		Weeks 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 and 96.
Change From Baseline in Mean log10 HBV RNA Off-Treatment		Weeks 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 and 96.
Change From Baseline in Mean log10 Hepatitis B Core-related Antigen (HBcrAg) Off-Treatment		Weeks 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 and 96.

Collaborators and Investigators

• Sponsor: Assembly Biosciences
• Collaborators: Arbutus Biopharma Corporation

Publications and helpful links

General Publications

• Ligat G, Verrier ER, Nassal M, Baumert TF. Hepatitis B virus-host interactions and novel targets for viral cure. Curr Opin Virol. 2021 Aug;49:41-51. doi: 10.1016/j.coviro.2021.04.009. Epub 2021 May 22.

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2021
• Primary Completion (Actual): March 30, 2023
• Study Completion (Actual): March 30, 2023

Study Registration Dates

• First Submitted: March 25, 2021
• First Submitted That Met QC Criteria: March 25, 2021
• First Posted (Actual): March 29, 2021

Study Record Updates

• Last Update Posted (Estimated): November 14, 2023
• Last Update Submitted That Met QC Criteria: October 23, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: cHBV; HBV; hepatitis B; vebicorvir; VBR; AB-729
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Disease Attributes; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Chronic Disease; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Entecavir
• Other Study ID Numbers: ABI-H0731-204

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No