A Phase 2 Study to Evaluate the Safety, Tolerability, and Efficacy of Regimens Containing VIR-2218, VIR-3434, and/or PEG-IFNα in Subjects with Chronic Hepatitis B Virus Infection

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• 1. Significant fibrosis or cirrhosis as defined by having either a FibroScan result of > 8.5 kPa at screening or a liver biopsy within 1 year with Metavir F3 fibrosis or F4 cirrhosis. 2. History of clinically significant liver disease from non-HBV etiology 3. History of hepatic decompensation, including ascites, hepatic encephalopathy, and/or esophageal or gastric varices 4. History of immune complex disease 5. History of an autoimmune disorder 6. History of HBV-related extrahepatic disease, including but not limited to HBV-related rash, arthritis, or glomerulonephritis 7. History of allergic reactions, hypersensitivity, or intolerance to monoclonal antibodies, antibody fragments, or any excipients of VIR-3434 8. History of anaphylaxis 9. History of malignancy diagnosed or treated within 5 years (localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to screening); subjects under evaluation for malignancy are not eligible. 10. History of bone marrow or solid organ transplant 11. Known active infection other than chronic HBV infection or any clinically significant acute condition such as fever (> 38° C) or acute respiratory illness within 7 days prior to Day 1 12. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV). Subjects who are HCV antibody or HDV antibody positive, but have a documented negative HCV RNA or HDV RNA, respectively, are eligible.
• 13. Creatinine clearance (CLcr) < 30 mL/min as calculated by the Cockcroft-Gault formula at screening 14. Subject has the following laboratory parameters at screening by laboratory testing: a. ALT or aspartate aminotransferase (AST) > 3x ULN b. Direct bilirubin or INR > ULN 15. Regular consumption of more than 10 units of alcohol per week (1 unit = 1 glass of wine [125 mL] = 1 measure of spirits [30 mL] = one-half pint of beer [284 mL]), or more than 2 units of alcohol per day 16. History or clinical evidence of alcohol or drug abuse within the 12 months before screening or a positive drug screen at screening unless it can be explained by a prescribed medication (the diagnosis and prescription must be approved by the investigator). Note: cannabis use is permitted 17. Use of any of the following systemic medications within 14 days before study drug administration and throughout the study: a. Paracetamol (acetaminophen) ≥ 3 g/day b. Isoniazid c. Systemic steroids (prednisone equivalent of > 10 mg/day) or other immunosuppressive agents (Note: corticosteroid administration for the treatment of immune-mediated AEs is allowed.) d. Parts A, C, and D only: theophylline e. Parts A, C, and D only: methadone
• 18. Received an investigational agent within 90 days or 5 half-lives (if known), whichever is longer, before study drug administration or are active in the follow-up phase of another clinical study involving interventional treatment. Subjects must also agree not to take part in any other interventional study at any time during their participation in this study, inclusive of the Follow-Up Period and NRTI Discontinuation Monitoring Period. Note: Participants who previously enrolled in Cohort 1d of the VIR-2218-1001 study are eligible for Cohort 2b only. 19. Receipt of an oligonucleotide (eg, siRNA, antisense oligonucleotide) with activity against HBV within 48 weeks before study drug administration Note: Participants who previously enrolled in Cohort 1d of the VIR-2218-1001 study and received VIR-2218 are eligible for Cohort 2b only. 20. Receipt of VIR-3434 within 24 weeks prior to Day 1 21. Any clinically significant medical or psychiatric condition that may interfere with study treatment, assessment, or compliance with the protocol or otherwise makes the subject unsuitable for participation in the study, as determined by the investigator. 22. Parts A, C, and D only: Known hypersensitivity or contraindication to an interferon product 23. Parts A, C, and D only: Current or prior history of psychosis, bipolar disorder, schizophrenia, moderate-severe depression, suicide ideation, attempt, or gesture, or high risk for suicide 24. Parts A, C, and D only: Current or prior history of clinically significant retinal disease
• 25. Parts A, C, and D only: Current or prior history of chronic uncontrolled hypoglycemia, or uncontrolled hyperglycemia/diabetes (defined as HbA1c ≥ 8%) at screening 26. Parts A, C, and D only: Current or prior history of colitis 27. Parts A, C, and D only: Serum lipase ≥ 2 times the ULN 28. Parts A, C, and D only: Thyroid stimulating hormone (TSH) and free T4 above the ULN or below the lower limit of normal (LLN) 29. Parts A, C, and D only: Platelets < 90,000 cells/mm3 30. Parts A, C, and D only: Absolute neutrophil count (ANC) < 1,500 cells/mm3 31. Clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening (as determined by the investigator)