An Efficacy and Safety Study of a Combination of JNJ-73763989, Nucleos(t)Ide Analogs (NA), and a Programmed Cell Death Protein Receptor-1 (PD-1) Inhibitor in Chronic Hepatitis B Participants

Study Overview
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Brief Summary
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The purpose of this study is to evaluate efficacy of the study intervention, based on hepatitis B surface antigen (HBsAg) levels at follow-up (FU) Week 24.

Detailed Description
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JNJ-73763989 (JNJ-3989) is a small interfering ribonucleic acid (siRNA) targeting all hepatitis B virus (HBV) messenger ribonucleic acid (mRNAs). The programmed cell death protein receptor-1 (PD-1) inhibitor aims at preventing the interaction of PD-1 with its ligands. The purpose of this study to determine whether at least one of the combination regimens of JNJ-3989 + PD-1 inhibitor + Nucleos(t)ide analog (NA) is more efficacious than JNJ-3989 + NA treatment. This study will be conducted in 3 periods: screening period, treatment period and follow-up (FU) period. Safety assessments will include adverse events (AEs), serious AEs, clinical safety laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. Total duration of individual participation will be up to 78 weeks (including screening period).

Official Title
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A Phase 2 Open-label Trial to Evaluate Safety, Efficacy, Tolerability, and Pharmacodynamics of a Combination of JNJ-73763989, Nucleos(t)Ide Analogs, and a PD-1 Inhibitor in Chronic Hepatitis B Patients

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: JNJ-73763989
* Drug: PD-1 inhibitor
* Drug: Tenofovir Disoproxil
* Drug: Tenofovir Alafenamide
* Drug: Entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have chronic hepatitis B virus (HBV) infection Participants must have fibroscan liver stiffness measurement less than or equal to (<=) 9.0 kilopascal (kPa) or a liver biopsy result classified as metavir F0-F2 Exclusion Criteria: Participants with evidence of hepatitis A virus infection (hepatitis A antibody immunoglobulin IgM), hepatitis C virus (HCV) infection (HCV antibody), hepatitis D virus (HDV) infection (HDV antibody), hepatitis E virus (HEV) infection (hepatitis E antibody IgM), or human immunodeficiency virus type 1 (HIV-1) or human immunodeficiency virus type 2 (HIV-2) infection (laboratory confirmed) at screening History or evidence of clinical signs or symptoms of hepatic decompensation, including but not limited to portal hypertension, ascites, hepatic encephalopathy, esophageal varices Participants with history or signs of cirrhosis or portal hypertension or signs of hepatocellular carcinoma (HCC) or clinically relevant renal abnormalities Participants with personal/familial history/indicative of immune-mediated disease risk

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: JNJ-73763989 + PD-1 Inhibitor + Nucleos(t)ide analog (NA)<br>Participants will receive JNJ-73763989 subcutaneous (SC) injections and single dose of programmed cell death protein receptor-1 (PD-1) inhibitor as intravenous (IV) infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, tenofovir alafenamide [TAF] or entecavir [ETV]). | Drug: JNJ-73763989<br>* JNJ-73763989 will be administered subcutaneously.<br>* Other names: JNJ-3989;Drug: PD-1 inhibitor<br>* PD-1 inhibitor will be administered as IV infusion.<br>Drug: Tenofovir Disoproxil<br>* Tenofovir disoproxil film-coated tablets will be administered orally.<br>Drug: Tenofovir Alafenamide<br>* TAF film-coated tablets will be administered orally.<br>Drug: Entecavir<br>* ETV film-coated tablets will be administered orally.<br>|
| Experimental: Arm 2: JNJ-73763989 + PD-1 Inhibitor + NA<br>Participants will receive JNJ-73763989 SC injections and multiple doses of PD-1 inhibitor as IV infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, TAF or ETV). | Drug: JNJ-73763989<br>* JNJ-73763989 will be administered subcutaneously.<br>* Other names: JNJ-3989;Drug: PD-1 inhibitor<br>* PD-1 inhibitor will be administered as IV infusion.<br>Drug: Tenofovir Disoproxil<br>* Tenofovir disoproxil film-coated tablets will be administered orally.<br>Drug: Tenofovir Alafenamide<br>* TAF film-coated tablets will be administered orally.<br>Drug: Entecavir<br>* ETV film-coated tablets will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve Hepatitis B Surface Antigen (HBsAg) Seroclearance |  | Follow up Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Experience Adverse Events (AEs) of Interest | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. AEs of interest are significant AEs that are judged to be of special interest because of clinical importance, known class effects or based on nonclinical signals. | Up to Week 72 | 
| Number of Participants with Adverse Events (AEs) by Severity | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. Severity of adverse event will be graded by using Division of AIDS (DAIDS) grading scale ranges from Grade 1 to Grade 5. Grade 1 indicates a mild event, Grade 2 indicates a moderate event, Grade 3 indicates a severe event, Grade 4 indicates a potentially life-threatening event, Grade 5 indicates death. | Up to Week 72 | 
| Number of Participants with Immune Related Adverse Events (AEs) by Severity | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. Severity of immune related AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event. | Up to Week 72 | 
| Number of Participants with Abnormalities in Vital Signs, Physical Examinations, Clinical Laboratory Tests, 12-lead Electrocardiograms (ECGs) | Number of participants with abnormalities in vital sign measurements (including pulse rate and blood pressure, both systolic and diastolic); physical examinations (including height at screening, body weight, skin examination, general appearance, eyes, ears, nose, throat, cardiovascular system, respiratory system, gastro-intestinal system and mucous; clinical laboratory tests (including hematology, clinical chemistry and urinalysis); 12-lead ECGs (heart rate, PR, QRS, QT) will be reported. | Up to Week 72 | 
| Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels |  | Baseline up to Week 72 | 
| Percentage of Participants with Change in HBsAg Levels Below/Above Different Cut-offs Over Time |  | Up to Week 72 | 
| Percentage of Participants with HBsAg Seroclearance/Seroconversion |  | Up to Week 72 | 
| Time to Achieve HBsAg Seroclearance/ Seroconversion | Time to achieve HBsAg seroclearance/ seroconversion will be reported. | Up to Week 72 | 
| Change from Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels |  | Baseline up to Week 72 | 
| Percentage of Participants with HBV DNA and Hepatitis B e Antigen (HBeAg) Levels Below/above Different Cut-offs | Percentage of participants with HBV DNA and HBeAg Levels below/above different cut-offs will be reported. | Up to Week 72 | 
| Percentage of Participants with Virologic Breakthrough | Percentage of participants with virologic breakthrough (confirmed on-treatment HBV DNA increase by greater than [>]1 log10 international unit per milliliter [IU/mL] from nadir or confirmed on-treatment HBV DNA level >200 IU/mL in participants who had HBV DNA level less than [<] lower limit of quantification [LLOQ] of the HBV DNA assay) will be reported. | Up to Week 72 | 
| Plasma Concentrations of JNJ-3989 and its Metabolites (JNJ-3924 and JNJ-3976) | Plasma concentrations of JNJ-3989 and its metabolites (JNJ-3924 and JNJ-3976) will be reported. | Up to Week 24 | 
| Plasma Concentrations of NA (Tenofovir disoproxil, Tenofovir Alafenamide [TAF] or Entecavir [ETV]) (Optional) | Plasma concentrations of NA (tenofovir disoproxil, TAF or ETV) will be reported. | Up to Week 24 | 
| Serum Concentrations of PD-1 Inhibitor (Optional) | Serum concentrations of PD-1 inhibitor will be reported. | Up to Week 24 |