A Study Evaluating Treatment Intensification With ABI-H0731 in Participants With Chronic Hepatitis B Infection on Nucleos(t)Ide Reverse Transcriptase Inhibitors

• ABI-H0731 (Drug): Participants will receive ABI-H0731 tablets orally once daily
• Placebo (Drug): Participants will receive placebo to ABI-H0731 tablets orally once daily
• NrtI (Drug), also known as Nucleos(t)ide reverse transcriptase inhibitor: Entecavir (ETV), tenofovir alafenamide (TAF), or tenofovir disoproxil fumarate (TDF) SOC according to the respective package insert

Primary outcomes

• Number of Participants With an Adverse Event [Baseline and up to 5 months]
• Number of Participants With Premature Discontinuation of Treatment [Baseline and up to 5 months]
• Number of Participants With a Laboratory Abnormality [Baseline and up to 5 months]
• Number of Participants With HBV DNA <Lower Limit of Quantification (LLOQ) at Week 48 [Week 48]

Secondary outcomes

• Mean Change From Baseline in log10 HBV DNA [Baseline and up to 5 months]
• Number of Participants With HBV DNA <LLOQ at Each Timepoint [Baseline and up to 5 months]
• Number of Participants With HBV DNA <Limit of Detection (LOD) [Baseline and up to 5 months]
• Mean Change From Baseline in log10 HBV Pregenomic RNA (pgRNA) [Baseline and up to 5 months]
• Number of Participants With HBV pgRNA <LLOQ [Baseline and up to 5 months]
• Mean Change From Baseline in log10 Serum Hepatitis B 'e' Antigen (HBeAg) [Baseline and up to 5 months]
• Mean Change From Baseline in log10 Serum Hepatitis B Core-related Antigen (HBcrAg) [Baseline and up to 5 months]
• Mean Change From Baseline in log10 Serum Hepatitis B Surface Antigen (HBsAg) [Baseline and up to 5 months]
• Number of Participants With Normalized Alanine Aminotransferase (ALT) [Baseline and up to 5 months]
• Plasma Concentrations of ABI-H0731 [Baseline and up to 5 months]
• Plasma Concentrations of Entecavir [Baseline and up to 5 months]
• Incidence of HBV Variants Among Participants With Evidence of Non-response to Treatment [Baseline and up to 5 months]

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Body mass index (BMI) 18 to 36 kg/m\^2 and a minimum body weight of 45 kg (inclusive)
* In good general health except for chronic hepatitis B (CHB)
* HBeAg positive or HBeAg negative chronic hepatitis B
* HBV DNA >LLOQ using a commercially available assay with LLOQ=20 IU/mL
* On a stable NrtI regimen (ETV, TDF or TAF) for more than 12 months
* Lack of cirrhosis or advanced liver disease

Exclusion Criteria:

* Current or prior treatment for CHB with lamivudine, telbivudine, adefovir, HBV core inhibitor, or previous treatment with an investigational agent for HBV infection
* Presence of substitutions in the HBV polymerase coding region which may confer reduced susceptibility to NrtIs
* Co-infection with human immunodeficiency virus, hepatitis A virus, hepatitis C virus, hepatitis E virus, or hepatitis D virus
* Females who are lactating or wish to become pregnant during the course of the trial
* History or evidence of advanced liver disease or hepatic decompensation
* Clinically significant cardiac disease including poorly-controlled or unstable hypertension; pulmonary disease; chronic or recurrent renal or urinary tract disease; liver disease other than CHB; 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 trial participation
* History of hepatocellular carcinoma (HCC)
* Exclusionary laboratory parameters at Screening:

  * Platelet count <100,000/mm\^3
  * Albumin <lower limit of normal
  * Total bilirubin >1.2 × upper limit of normal (ULN)
  * Direct bilirubin >1.2 × ULN
  * ALT >10 × ULN
  * Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is >ULN but <100 ng/mL, the participant is eligible if a hepatic imaging trial prior to initiation of study drug reveals no lesions indicative of possible HCC.
  * International Normalized Ratio >1.5 × ULN
  * Glomerular filtration rate <50 mL/min/1.73 m\^2 by Chronic Kidney Disease Epidemiology Collaboration equation
  * Any other laboratory abnormality deemed clinically significant by the Sponsor or the Investigator.

Participant flow

Outcome results

• Number of Participants With an Adverse Event (Primary), Number, participants: ABI-H0731 + SOC NrtI 0; Placebo + SOC NrtI 1
• Number of Participants With Premature Discontinuation of Treatment (Primary), Number, participants: ABI-H0731 + SOC NrtI 1; Placebo + SOC NrtI 1
• Number of Participants With a Laboratory Abnormality (Primary), Number, participants: ABI-H0731 + SOC NrtI 1; Placebo + SOC NrtI 1
• Number of Participants With HBV DNA <Lower Limit of Quantification (LLOQ) at Week 48 (Primary)
• Mean Change From Baseline in log10 HBV DNA (Secondary)
• Number of Participants With HBV DNA <LLOQ at Each Timepoint (Secondary)
• Number of Participants With HBV DNA <Limit of Detection (LOD) (Secondary)
• Mean Change From Baseline in log10 HBV Pregenomic RNA (pgRNA) (Secondary)
• Number of Participants With HBV pgRNA <LLOQ (Secondary)
• Mean Change From Baseline in log10 Serum Hepatitis B 'e' Antigen (HBeAg) (Secondary)
• Mean Change From Baseline in log10 Serum Hepatitis B Core-related Antigen (HBcrAg) (Secondary)
• Mean Change From Baseline in log10 Serum Hepatitis B Surface Antigen (HBsAg) (Secondary)
• Number of Participants With Normalized Alanine Aminotransferase (ALT) (Secondary)
• Plasma Concentrations of ABI-H0731 (Secondary)
• Plasma Concentrations of Entecavir (Secondary)
• Incidence of HBV Variants Among Participants With Evidence of Non-response to Treatment (Secondary)

Adverse events

Time frame: Baseline and up to 5 months

Other adverse events by term

Limitations and caveats: Study ABI-H0731-205 was terminated early by the study Sponsor for strategic reasons to prioritize research and development efforts on finite and curative HBV therapies. At the time of early termination, only 2 participants were enrolled, both of which discontinued their assigned study treatment early due to the study being terminated early by the Sponsor. As a result, the primary outcome of number of participants with HBV DNA <LLOQ at Week 48 could not be assessed.

• Study Protocol and Statistical Analysis Plan (PDF, 2020-09-08)

• Steven Knox, Study director, Assembly Biosciences