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

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.

• VBR (Drug), also known as Vebicorvir, ABI-H0731: VBR is an HBV core protein inhibitor. Participants will receive VBR 300 mg tablets orally once daily (QD).
• AB-729 (Drug): 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.
• SOC NrtI (Drug), also known as Entecavir (ETV), Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide (TAF): Participants will receive their SOC NrtI (ETV, TDF or TAF) tablet orally as per approved package insert.

Primary outcomes

• 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 outcomes

• Change From Baseline in Mean log10 Serum Hepatitis B Surface Antigen (HBsAg) On-Treatment [Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56.]: 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.
• 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 [Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56.]: 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.
• 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]
• 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) 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.]

Sex: All, ages: 18 Years to 50 Years

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.

Participant flow

Outcome results

• Number of Participants With One or More Adverse Events (AEs) (Primary), Count of participants, Participants: VBR + AB-729 + SOC NrtI 26; VBR + SOC NrtI 12; AB-729 + SOC NrtI 12
• Number of Participants With Premature Treatment Discontinuation Due to AEs (Primary), Count of participants, Participants: VBR + AB-729 + SOC NrtI 3; VBR + SOC NrtI 1; AB-729 + SOC NrtI
• Number of Participants With One or More Abnormal Laboratory Result (Primary), Count of participants, Participants: VBR + AB-729 + SOC NrtI 30; VBR + SOC NrtI 16; AB-729 + SOC NrtI 16
• Change From Baseline in Mean log10 Serum Hepatitis B Surface Antigen (HBsAg) On-Treatment (Secondary), Mean, log10 IU/mL: VBR + AB-729 + SOC NrtI -0.3 +/- .42; VBR + SOC Nrtl 0 +/- 0.07; AB-729 + SOC NrtI -0.2 +/- .26
• Number of Participants With Serum HBsAg Below the Lower Limit of Quantitation (<LLOQ) (Secondary)
• Number of Participants With HBV Deoxyribonucleic Acid (DNA) Not Detected (<5 IU/mL) (Secondary)
• Number of Participants With HBV Ribonucleic Acid (RNA) <LLOQ (Secondary)
• Change From Baseline in Mean log10 HBV RNA On-Treatment (Secondary), Mean, log10 U/mL: VBR + AB-729 + SOC NrtI -.6 +/- .75; VBR + SOC NrtI -.2 +/- .7; AB-729 + SOC NrtI -.4 +/- .48
• Change From Baseline in Mean log10 Hepatitis B Core-related Antigen (HBcrAg) On-Treatment (Secondary), Mean, log10 U/mL: VBR + AB-729 + SOC NrtI -0.4 +/- .7; VBR + SOC NrtI 0 +/- .58; AB-729 + SOC NrtI -0.3 +/- .53
• Number of Participants With HBsAg Seroconversion (Secondary)
• Number of Participants With Normal Alanine Aminotransferase (ALT) (Secondary)
• Plasma Levels of VBR (Secondary)
• Plasma Levels of AB-729 (Secondary)
• Plasma Levels of SOC NrtI (ETV, TDF, TAF) (Secondary)
• Change From Baseline in Mean log10 Serum Hepatitis B Surface Antigen (HBsAg) Off-Treatment (Secondary), Mean, log10 IU/mL: VBR + AB-729 + SOC NrtI (Discontinued All) -1.9 +/- .51; VBR + AB-720 + SOC NrtI (Continued NrtI Only) -1.6 +/- .53; VBR + SOC Nrtl (Discontinued All) ; VBR + SOC Nrtl (Continued NrtI Only) 0 +/- .09; AB-729 + SOC NrtI (Discontinued All) -1.8 +/- .75; AB-729 + SOC NrtI (Continued NrtI Only) -1.8 +/- .62
• Change From Baseline in Mean log10 HBV RNA Off-Treatment (Secondary), Mean, log10 U/mL: VBR + AB-729 + SOC NrtI (Discontinued All) -0.6 +/- .83; VBR + AB-720 + SOC NrtI (Continued NrtI Only) -0.8 +/- 1.03; VBR + SOC Nrtl (Discontinued All) ; VBR + SOC Nrtl (Continued NrtI Only) -0.1 +/- .57; AB-729 + SOC NrtI (Discontinued All) -1.1 +/- .61; AB-729 + SOC NrtI (Continued NrtI Only) -0.9 +/- 1.05
• Change From Baseline in Mean log10 Hepatitis B Core-related Antigen (HBcrAg) Off-Treatment (Secondary), Mean, log10 U/mL: VBR + AB-729 + SOC NrtI (Discontinued All) -0.3 +/- .46; VBR + AB-720 + SOC NrtI (Continued NrtI Only) -0.5 +/- .81; VBR + SOC Nrtl (Discontinued All) ; VBR + SOC Nrtl (Continued NrtI Only) .1 +/- .48; AB-729 + SOC NrtI (Discontinued All) -0.1 +/- .18; AB-729 + SOC NrtI (Continued NrtI Only) -0.6 +/- .70

Adverse events

Time frame: Baseline and at pre-specified time points up to 96 weeks

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Study ABI-H0731-204 was terminated early by the study Sponsor for strategic reasons to prioritize research and development efforts on finite and curative HBV therapies. As a result, not all subjects completed Week 96 and some outcome measures were impacted.

• Results publication: 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. PMID 34029994

• Study Protocol and Statistical Analysis Plan (PDF, 2023-05-22)