Combination therapy for treating hepatitis d virus (HDV) infection

Abstract

Methods for treating hepatitis D virus (HDV) infection and / or an HDV-associated disease using combination therapies, and related compositions for use in such methods.

Description

COMBINATION THERAPY FOR TREATING HEPATITIS D VIRUS (HDV)INFECTIONREFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0001] This application contains a Sequence Listing, which has been submitted electronically in xml format and is hereby incorporated by reference in its entirety. Said xml copy, created on January 7, 2026, is named SeqList-368561-45302.xml and is 43,809 bytes in size.BACKGROUND

[0002] Hepatitis D, also known as "delta hepatitis," is a viral infection caused by the hepatitis D virus (HDV). HDV is a defective RNA satellite virus that does not encode its own envelope proteins and is dependent on the expression of the hepatitis B virus (HBV) surface antigen (HBsAg) to complete its life cycle and produce infectious HDV virions. Thus, HDV must either coinfect or superinfect with HBV.

[0003] Approximately 300 million people are living with chronic HBV infection worldwide (Polaris Observatory Collaborators, Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study, Lancet Gastroenterol Hepatol. 2018 Jun, 3(6):383-403) and are at risk of serious sequelae, including cirrhosis, liver failure, hepatocellular carcinoma (HCC). Worldwide prevalence of HDV has been estimated in 3 recent meta-analyses. with results ranging from 12 million people (Stockdale AJ et al., The global prevalence of hepatitis D virus infection: Systematic review and meta-analysis, J Hepatol. 2020 Sep, 73(3):523-532) to 60 to 72 million (Chen HY et al., Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut 2019 Mar, 68(3):512-521; Miao Z et al., Estimating the Global Prevalence, Disease Progression, and Clinical Outcome of Hepatitis Delta Virus Infection, J Infect Dis. 2020 Apr 27, 221(10): 1677-1687). HDV infection is the most aggressive form of viral hepatitis due to rapid progression to liver failure, cirrhosis, HCC, and death observed in persons with chronic HBV / HDV coinfection (Lee AU and Lee C, Hepatitis D Review: Challenges1181072933.1for the Resource-Poor Setting, Viruses. 2021 Sep 23, 13(10): 1912; Stockdale et al., 2020, supra). Among persons with chronic HDV infection, 85 to 95% may develop cirrhosis and liver failure within 10 years of infection with some developing these complications as early as 1 to 2 years after infection (-15%) (Kamili S et al., Delta hepatitis: Toward improved diagnostics, Hepatology 2017 Dec, 66(6):1716-1718; NIH, National Institute of Diabetes and Digestive and Kidney Diseases, United States 2017, Department of Health and Human Services, Accessed April 10, 2020; Rizzetto M, Hepatitis D Virus: Introduction and Epidemiology, Cold Spring Harb Perspect Med. 2015 Jul 1, 5(7), a021576; WHO, Hepatitis B. www.who.int / news-room / factsheets / detail / hepatitis-b, Published July 2021, Accessed April 10, 2022). Notably, approximately 50% of HDV -infected patients are cirrhotic at diagnosis (Fattovich G et al., Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B, J Infect Dis. 1987 May, 155(5):931-5).

[0004] Hepatitis B virus (HBV) is a DNA virus that infects, replicates, and persists in human hepatocytes (Protzer U et al., Living in the liver: hepatic infections, Nature Reviews Immunology 2012, 12:201-213). The small viral genome (3.2 kb), consists of partially double-stranded, relaxed-circular DNA (rcDNA) and has 4 open reading frames encoding 7 proteins: HBcAg (HBV core antigen, viral capsid protein), HBeAg (hepatitis B e-antigen), HBV Pol / RT (polymerase, reverse transcriptase), PreSl / PreS2 / HBsAg (large, medium, and small surface envelope glycoproteins), and HBx (HBV x antigen, regulator of transcription required for the initiation of infection) (Seeger C et al., Molecular biology of hepatitis B virus infection. Virology 2015, 479-480:672-686; Tong S et al., Overview of viral replication and genetic variability, Journal of Hepatology, 2016, 64(1): S4-S16).

[0005] In hepatocytes, rcDNA, the form of HBV nucleic acid that is introduced by the infection virion, is converted into a covalently closed circular DNA (cccDNA), which persists in the host cell's nucleus as an episomal chromatinized structure (Allweiss L et al., The Role of cccDNA in HBV Maintenance, Viruses 2017, 9: 156). The cccDNA serves as a transcription template for all viral transcripts (Lucifora J et al., Attacking hepatitis B virus cccDNA — The holy grail to hepatitis B cure, Journal of2181072933.1Hepatology 2016, 64(1):S41-S48). Pregenomic RNA (pgRNA) transcripts are reverse transcribed into new rcDNA for new virions, which are secreted without causing cytotoxicity. In addition to infectious virions, infected hepatocytes secrete large amounts of genome-free subviral particles that may exceed the number of secreted virions by 10,000-fold (Seeger et al., 2015, supra). Random integration of the virus into the host genome can occur as well, a mechanism that contributes to hepatocyte transformation (Levrero M et al., Mechanisms of HBV-induced hepatocellular carcinoma, Journal of Hepatology 2016, 64(l): S84-S101). HBV persists in hepatocytes in the form of cccDNA and integrated DNA (intDNA).

[0006] Hepatitis B infection is characterized by serologic viral markers and antibodies. In acute resolving infections, the virus is cleared by effective innate and adaptive immune responses that include cytotoxic T cells leading to death of infected hepatocytes, and induction of B cells producing neutralizing antibodies that prevent the spread of the virus (Bertoletti A, Adaptive immunity in HBV infection, Journal of Hepatology 2016, 64(1): S71-S83; Maini MK et al., The role of innate immunity in the immunopathology and treatment of HBV infection, Journal of Hepatology 2016, 64(1): S60-S70; Li Y et al., Genome-wide association study identifies 8p21.3 associated with persistent hepatitis B virus infection among Chinese, Nature Communications 2016, 7:11664). In contrast, chronic infection is associated with T and B cell dysfunction, mediated by multiple regulatory mechanisms including presentation of viral epitopes on hepatocytes and secretion of subviral particles (Bertoletti et al., 2016, supra; Maini et al., 2016, supra; Burton AR et al., Dysfunctional surface antigen specific memory B cells accumulate in chronic hepatitis B infection, EASL International Liver Congress, Paris, France 2018). Thus, the continued expression and secretion of viral proteins due to cccDNA persistence in hepatocytes is considered a key step in the inability of the host to clear the infection.

[0007] Treatment options for HDV infection are limited to pegylated interferon alpha (PEG-IFNa) and buleviritide. PEG-IFNa leads to sustained virologic response (SVR (clearance of serum HDV maintained 6 months after stopping treatment)) in only around 25 to 30% of individuals treated for 48 weeks. Late relapses were observed in3181072933.1approximately 50% of those patients reducing the long-term efficacy to approx. 15% (Abbas Z et al., Interferon alpha for chronic hepatitis D. Cochrane Database Syst Rev.2011 Dec 7, 201 l(12): CD006002; Heidrich B et al., Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta, Hepatology 2014;60:87–97). Current guidelines from the American Association for the Study of Liver Diseases (AASLD), the Asia Pacific Association for the Study of the Liver (APASL) and the European Association for the Study of the Liver (EASL) recommend administering PEG-IFNa for at least 48 weeks to patients with chronic HDV infection (European Association for the Study of the Liver (EASL), EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug, 67(2):370-398; Sarin SK et al., Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016 Jan, 10(1): 1-98; TerraultNA et al., Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance, Hepatology 2018 Apr, 67(4):1560-1599). In addition to low SVR rates, the major adverse reactions of PEG-IFNa therapy are well described and PEG-IFNa is contraindicated in patients with autoimmune diseases, major psychiatric syndromes and Child-Pugh-Turcotte (CPT)-B or CPT-C stage cirrhotic patients (Rizzetto M, Hepatitis D Virus: Introduction and Epidemiology, Cold Spring Harb Perspect Med. 2015 Jul 1, 5(7):a021576; Sleijfer S et al., Side effects of interferonalpha therapy, Pharm World Sci. 2005 Dec, 27(6):423-31). Further limiting its usefulness, reduced PEG-IFNa efficacy has been observed when treating cirrhotic patients with chronic HDV (Gunsar F et al.. Two-year interferon therapy with or without ribavirin in chronic delta hepatitis, Antivir Ther. 2005, 10(6):721-6).Limitations about the use of PEG-IFNa in cirrhotic HDV patients is particularly notable as 50% of HDV-infected patients are cirrhotic at diagnosis (Fattovich et al., 1987, supra). These limitations and poor efficacy of current agents highlights an unmet need for patients with chronic HDV infection in all stages of the disease. Bulevirtide (BLV), an entry inhibitor that targets the sodium taurocholate co-transporting polypeptide (NTCP) receptor, has conditional approval in the EU for chronic HDV therapy. Interim results from the Phase 3 MYR301 study indicate that after 24 weeks of 2 mg daily4181072933.1subcutaneous (SC) dose of BLV, 36.7% of participants achieve the combined virological and biochemical endpoint. Nucleoside reverse transcriptase inhibitors (NRTI) therapy can suppress HBV replication but do not directly impact HBsAg production, intrahepatic HDV replication, or HDV viremia.BRIEF SUMMARY

[0008] In some aspects, the present disclosure provides methods of treating hepatitis D virus (HDV) infection or an HDV-associated disease in a subject in need thereof, comprising administering to the subject: (a) tobevibart, an anti-HBV antibody; and (b) elebsiran, an siRNA that targets an HBV mRNA. In some embodiments, the method is for preventing, eliminating, or reducing the number of or frequency of ALT flares in the subject. In some embodiments, the subject has a normal ALT level (less than the upper limit of normal) before treatment. In some embodiments, the antibody and siRNA are administered for up to 48 weeks to up to 96 weeks. In some embodiments, treatment is discontinued if the subject does not have detectable HDV RNA. In some aspects, compositions for use in treatment and compositions for use in the manufacture of medicaments are provided.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 depicts the study schema for the clinical study in Example 1. Eligible participants include noncirrhotic and compensated cirrhotic subjects with chronic hepatitis D virus (HDV) infection and elevated alanine aminotransferase (ALT) levels and on nucleoside reverse transcriptase inhibitors (NRTIs). **Primary Endpoint: HDV RNA < lower limit of quantification (LLOQ), target not detected (TND) and ALT normalization at Week 48 for Arm 1 versus at Week 12 for Arm 2 (Delayed Treatment Comparator). Key Secondary Endpoint: HDV RNA < LLOQ, TND Week 48 for Arm 1 versus at Week 12 for Arm 2.

[0010] Figures 2A-2C show the Schedule of Activities for the study intervention treatment period with tobevibart+elebsiran (Screen to Week 48 for Arm 1; Week 12 to Week 60 for Arm 2) for the clinical study in Example 1. ADA = anti-drug5181072933.1antibodies; AE = adverse event; CBP = childbearing potential; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; D = Day; ECG = electrocardiogram; ECI = events of clinical interest; EQ-5D-5L = EuroQol 5-Dimension 5-Level; ET = early termination; HAV = hepatitis A virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; HIV = human immunodeficiency virus; HL A = human leukocyte antigen; ICF = informed consent form; NAb = neutralizing antibodies; PD = pharmacodynamics; PK = pharmacokinetic; PRO = patient-reported outcome; SAE = serious adverse event; SoA = schedule of activities; W = Week.aThe screening period can be extended to 7 weeks (49 days) for participants requiring a repeat assessment due to technical issues with the samples or delays in receiving HDV RNA results.bIf a participant prematurely discontinues study intervention, an ET visit should be scheduled as early as possible regardless of the target visit day / window, and the participant will then follow' the SoA show n in Figure 5 for the follow -up period.cPrior to first dose of study drug administration, participant eligibility' will be confirmed by the site.dA complete medical history will be taken at screening, including HBV and HDV genotype if available. Any changes to medical history should be reviewed and updated on Day 1.eA single 12-lead safety ECG will be recorded at screening and predose (within 1 hour) and should be measured prior to any vital sign measurements or blood draws scheduled on the same assessment day, in the supine position after the participant has rested comfortably for approximately 10 minutes. The preferred method for QTc correction is the Fredericia formula (QT / ∛RR).fVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study drug administration(s).gParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.hAfter signing of the ICF. but prior to DI, AEs related to protocol-mandated procedures and all SAEs wall be reported. All AEs / SAEs, regardless of cause or relationship, w ill be recorded for the entire duration of the study starting on6181072933.1DI for all participants.1Screening viral serology parameters include HAV, HCV, HEV, and HIV.JIf an Arm 2 participant who previously achieved ALT < ULN at any point is then found to have ALT > ULN at Week 12, another ALT sample should be drawn and tested within 7 days of the Week 12 ALT result.kIf a participant who previously achieved ALT < ULN at any point is then found to have ALT > ULN at this timepoint, another ALT sample should be drawn and tested within 7 days of the ALT result from this timepoint.1Additional samples may be collected at any time if immune complex disease is suspected.mCBP participants are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and a urine pregnancy test will be performed thereafter. Negative pregnancy test must be confirmed prior to study drug administration.nDoes not need to be performed if the participant has had a FibroScan® or liver biopsy in the 12 months prior to screening.

[0011] Figures 3A-3C show the Schedule of Activities for the study intervention treatment period with tobevibart+elebsiran (Week 52 to Week 240 for Arm 1; Week 64 to Week 252 for Arm 2) for the clinical study in Example 1. CBP = childbearing potential; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; D = Day; ECI = events of clinical interest; EOT = end of treatment; EQ-5D-5L = EuroQol 5-Dimension 5-Level; ET = early termination; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; IDMC = independent data monitoring committee; PRO = patient-reported outcome; Q4W = every 4 weeks; SoA = schedule of activities; W = Week.aTobevibart+elebsiran administration, pregnancy testing, AE and concomitant medications review and record, and laboratory ECI surveillance will occur Q4W (± 2 days) from Week 52 to Week 236 in Arm 1 and from Week 64 to Week 248 in Arm 2.bIf a participant prematurely discontinues study intervention, an ET visit should be scheduled as early as possible regardless of the target visit day / window, and the participant will then follow the SoA in Figure 5 for the follow-up period.cVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood7181072933.1sample collections and study drug administration(s).dParticipants will be monitored for laboratory' ECI, and additional assessments may be performed if indicated.eIf a participant who previously achieved ALT < ULN at any point is then found to have ALT > ULN at this timepoint, another ALT sample should be draw n and tested within 7 days of the ALT result from this timepoint.fAdditional samples may be collected at any time if immune complex disease is suspected.8CBP participants are required to have pregnancy tests. Negative urine pregnancy test must be confirmed prior to study drug administration.hResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.

[0012] Figures 4A-4B show the Schedule of Activities for the delayed treatment period (Screen to W8 for Arm 2) for the clinical study in Example 1. AE = adverse event; CBP = childbearing potential; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; D = Day; ECG = electrocardiogram; ECI = events of clinical interest; EQ-5D-5L = EuroQol 5-Dimension 5-Level; ET = early termination; HAV = hepatitis A virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; HIV = human immunodeficiency virus: HL A = human leukocyte antigen; ICF = informed consent form; PRO = patient-reported outcomes: SAE = serious adverse event; SoA = schedule of activities; W = Week.aThe screening period can be extended to 7 w eeks (49 days) for participants requiring a repeat assessment due to technical issues with the samples or delays in receiving HDV RNA results.11If a participant prematurely discontinues, an ET visit should be scheduled as early as possible regardless of the target visit day / window.cA complete medical history will be taken at screening, including HBV and HDV genotype if available. Any changes to medical history should be reviewed and updated on Day 1.dA single 12-lead safety ECG will be recorded should be measured prior to any vital sign measurements or blood draw s scheduled on the same8181072933.1assessment day, in the supine position after the participant has rested comfortably for approximately 10 minutes. The preferred method for QTc correction is the Fredericia formula (QT / ∛RR).eVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study drug administration(s).fParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.gAfter signing of the ICF, but prior to DI, AEs related to protocol-mandated procedures and all SAEs will be reported. All AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study starting on DI for all participants.hScreening viral serology parameters include HAV, HCV, HEV. and HIV.1Additional samples may be collected at any time if immune complex disease is suspected. J CBP participants are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and a urine pregnancy test will be performed thereafter. Negative pregnancy test must be confirmed prior to study drug administration.kDoes not need to be performed if the participant has had a FibroScan® or liver biopsy in the 12 months prior to screening.

[0013] Figure 5 shows the Schedule of Activities for the Follow-Up Period (Arm 1 and Arm 2) for the clinical study in Example 1. AE = adverse event; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; ECI = events of clinical interest; EQ-5D-5L = EuroQol 5-Dimension 5-Level; FD = follow-up day; FW = follow-up week; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; PK = pharmacokinetic; PRO = patient-reported outcomes; SAE = serious adverse event; SoA = schedule of activities.aFollow-up visits per this SoA to be initiated after the ET or EOT visit, for participants that received at least 1 dose of tobevibart or elebsiran.bVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study intervention administration(s).cParticipants9181072933.1will be monitored for laboratory ECI, and additional assessments may be performed if indicated.dFollowing initiation of study intervention, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.eCBP participants are required to have urine pregnancy tests.

[0014] Figure 6 depicts the study schema for the clinical study in Example 2. Eligible participants include noncirrhotic and compensated cirrhotic subjects with *Parti cipants in Arm 1 are eligible to interrupt treatment if HDV RNA < LLOQ, TND Week 48 through Week 96.

[0015] Figures 7A-7C show the Schedule of Activities for Screening through Week 96 (Arm 1 and Arm 2) for the clinical study in Example 2. ADA = anti-drug antibodies; AE = adverse event; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; BLV = bulevirtide; CBP = childbearing potential; CLDQ-HBV =Chronic Liver Disease Questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; D = Day; ECG = electrocardiogram; ECI = events of clinical interest; EQ-5D-5L = EuroQol 5-Dimension 5-Level; ET = early termination; HAV = hepatitis A virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic; PRO = patient-reported outcomes; Q4W = every 4 weeks; SAE = serious adverse event; SoA = Schedule of Activities; TSQM-9 = Treatment Satisfaction Questionnaire for Medication; W = Week.aThe screening period can be extended to 7 weeks (49 days) for participants requiring a repeat assessment due to technical issues with the samples or delays in receiving HDV RNA results.bIf a participant prematurely discontinues study intervention, an ET visit should be scheduled as early as possible regardless of the target visit day / window and continue to the safety follow-up period SoA. Participants in Arm 2 who opt out of switching study intervention at Week 24 and intend to continue BLV outside the study should complete the assessments as outlined in the ET visit and do not require any further follow-up.cParticipants should be instructed to withhold their usual BLV dose on Day 1 until they have been randomized. Participants who are10181072933.1randomized to Arm 2 will receive their first dose of tobevibart+elebsiran at the Week 24 visit and should be instructed to withhold their usual BLV dose on the day of the Week 24 visit.dFrom Day 1 to Week 24, tobevibart+elebsiran will be administered Q4W to participants in Arm 1 only. From Week 24 to Week 96, tobevibart+elebsiran will be administered Q4W to all participants.ePrior to study intervention administration on Day 1. participant eligibility will be confirmed by the site.fTraining on self-administration will be provided to participants on Day 1 and Day 1 dosing will occur on site when possible.gFor Arm 2 participants who opt to continue to receive BLV after Week 24, an ET visit should be completed at the Week 24 visit or as soon as possible. The most recent available data for HDV RNA (i.e., Week 20) should be used for treatment decision purposes.hFor participants who receive BLV supply from the Sponsor, BLV is to be dispensed even’ 4 weeks during scheduled site visits, with the requirement for daily injections. Additional supply may be dispensed to ensure adequate quantity for daily dosing upon Investigator and Sponsor approval.1To occur monthly per participants’ existing prescription, where available. Participants are required to bring back all BLV vials used since the last visit(s), and sites will perform accountability and compliance assessment. For locally sourced BLV, only used vials are required to be brought to the site for compliance assessment. For Sponsor supplied BLV, all used and unused vials must be brought back to the site for drug accountability.kParticipants who systematically interrupt tobevibart+elebsiran will not be dosed at Week 96. The HDV RNA results from the Week 92 visit (or the most recently available data) will be used to assess eligibility for tobevibart+elebsiran interruption. Participants who meet criteria to interrupt tobevibart+elebsiran will proceed to the SoA in Figures 8A-8B. Participants who do not meet criteria or who were randomized to Arm 2 will proceed to in Figures 9A-9B after Week 96 visit.1A complete medical history will be taken at screening, including HBV and HDV genoty pe if available. Any changes to medical history should be reviewed and updated prior to dosing on DI.m12-lead safety ECG will be recorded at screening and predose (within 1 hour) and should be measured prior to any vital sign measurements or blood draws scheduled on the same assessment day, in the supine position after the participant has rested comfortably for11181072933.1approximately 10 minutes. The preferred method for QTc correction is the Fredericia formula (QT / ∛RR).nVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study drug administration(s). ° Participants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.pAfter signing of the informed consent form (ICF), but prior to initiation of study intervention, AEs related to protocol-mandated procedures and all SAEs will be reported. Following initiation of study drug, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.qScreening viral serology parameters include HAV, HCV, HEV, and HIV.rAdditional samples may be collected at any time if immune complex disease is suspected.sCBP participants are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and urine pregnancy tests will be performed thereafter. Negative pregnancy test must be confirmed prior to study intervention administration. ‘ Resistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.uIncludes samples for ADA and neutralizing antibodies (NAb), as applicable for tobevibart and elebsiran. At visits where study intervention is administered, samples should be collected prior to dosing at each indicated timepoint. Additional samples for immunogenicity' analysis may be collected if a persistent drug related immunologic event is suspected.vSamples for tobevibart PK will be collected predose.wOn Day 1, samples for elebsiran PK will be collected predose, at 1.5 hours (± 15 minutes) and 4 hours (± 15 minutes) postdose. At Week 24 and Week 48, samples for elebsiran PK will be collected at 1.5 hours (± 15 minutes) and 4 hours (± 15 minutes) postdose.xPROs will be collected where available and approved. PROs are to be completed on site and, when possible, prior to any other study procedures or discussions with the Investigator.12181072933.1

[0016] Figures 8A-8B show the Schedule of Activities for Week 100 to Week 240 - Systematic Tobevibart+Elebsiran Interruption (Arm 1 only) for the clinical study in Example 2. ADA = anti-drug antibodies; AE = adverse event; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; CBP = childbearing potential; CPT = Child-Pugh-Turcotte; D = Day: ECI = events of clinical interest; ET = early termination; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic; SAE = serious adverse event; SoA = Schedule of Activities; W = Week.aParticipants who discontinue study during the treatment interruption period from Week 96 to Week 120 will have an ET visit and then be followed for an additional 24 weeks per the Safety Follow-up SoA in Figures 11A-11B. Participants who discontinue study during treatment interruption period after Week 120 will have an ET visit and do not require safety follow-up.bVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections).cParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.dFollowing initiation of study drug, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.eCBP participants are required to have urine pregnancy tests for 6 months following cessation of therapy.fResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.gIncludes samples for ADA and neutralizing antibodies (NAb), as applicable for tobevibart and elebsiran. Additional samples for immunogenicity analysis may be collected if a persistent drug related immunologic event is suspected.

[0017] Figures 9A-9B show the Schedule of Activities for Week 100 to Week 240-Continued Treatment Group (Arm 1 and Arm 2) for the clinical study in Example13181072933.12. AE = adverse event; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; CBP = childbearing potential; CPT = Child-Pugh-Turcotte; D = Day; ECI = events of clinical interest; ET = early termination; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; PBMC = peripheral blood mononuclear cells; SAE = serious adverse event; SoA = Schedule of Activities; W = Week.aIf a participant prematurely discontinues study intervention, an ET visit should be scheduled as early as possible regardless of the target visit day / window. Participants will then be monitored for safety follow-up per the SoA in Figures 11A-11B.bVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study drug administration(s).cParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.dFollowing initiation of study drug, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.eAdditional samples may be collected at any time if immune complex disease is suspected.fCBP participants are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and urine pregnancy tests will be performed thereafter. Negative pregnancy test must be confirmed prior to study intervention administration.gResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.

[0018] Figure 10 shows the Schedule of Activities for the Liver Biopsy Substudy (Optional Substudy, Arm 1 only) for the clinical study in Example 2. D = Day; HBsAg = hepatitis B surface antigen; HDV = hepatitis D virus; W = Week.aA pretreatment liver tissue sample will be collected during the screening window or up to Week 2 of the study.bAssessments will not be collected if the Liver Biopsy Substudy visit occurs on the same day as the regular study visit.cVital signs (blood pressure,14181072933.1pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. The assessments of vital signs must be performed before blood sample collections.

[0019] Figures 11A-11B show the Schedule of Activities of Activities for the Safety- Follow-Up Period for the clinical study in Example 2. ADA = anti-drug antibodies; AE = adverse event; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; BLV = bulevirtide; CBP = childbearing potential; CLDQ-HBV =Chronic Liver Disease Questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; ECI = events of clinical interest; EOS = end of study; EQ-5D-5L = EuroQol 5-Dimension 5-Level; FD = follow-up day; FW = follow-up week; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; NAb = neutralizing antibodies; PRO = patient-reported outcomes; SAE = serious adverse event; SoA = schedule of activities.aFollow-up visits per this SoA to be initiated after the last dose of study intervention. Participants who prematurely discontinue during the systematic treatment interruption do not require follow-up per this SoA.bVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collectionscParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.cFollowing initiation of study intervention, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.eCBP participants are required to have urine pregnancy tests.fResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.8Includes samples for ADA and NAb, as applicable for elebsiran and tobevibart.11PROs will be collected where available and approved. PROs are to be15181072933.1completed on site and when possible, prior to any other study procedures or discussions with the Investigator.

[0020] Figures 12A-12B depict the study schema for the clinical study in Example 3. Figure 12A shows the study design. Figure 12B shows the treatment options for BLV Group Participants at or After Week 52 (Arm 2).

[0021] Figures 13A-13C show the Schedule of Activities for the study intervention treatment period for participants receiving tobevibart+elebsiran (Arm 1; Screen to Week 48) for the clinical study in Example 3. ADA = anti-drug antibodies; AE = adverse event; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; CBP = childbearing potential; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child Pugh-Turcotte; D = Day; ECG = electrocardiogram; ECI = Events of Clinical Interest; EQ-5D-5L = EuroQol 5-Dimension 5-Level; ET = early termination; HAV = hepatitis A virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; ICF = informed consent form; NAb = neutralizing antibodies; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic; PRO = patient-reported outcomes; SAE = serious adverse event; SoA = Schedule of Activities; TSQM 9 = treatment satisfaction questionnaire for medication; W = Week.aThe screening period can be extended to 7 weeks (49 days) for participants requiring a repeat assessment due to technical issues with the samples or delays in receiving HDV RNA results.11If a participant prematurely discontinues study intervention, an ET visit should be scheduled as early as possible regardless of the target visit day / window, and the participant will then follow the SoA in Figure 19 for the Safety Follow-Up Period.cPrior to study drug administration on Day 1, participant eligibility will be confirmed by the site.dA complete medical history will be taken at screening, including HBV and HDV genotype if available. Any changes to medical history should be reviewed and updated prior to dosing on DI.eA single 12-lead safety ECG will be recorded at screening and pre-dose (within 1 hour) and should be measured prior to any vital sign measurements or blood draws scheduled on the same16181072933.1assessment day, in the supine position after the participant has rested comfortably for approximately 10 minutes. The preferred method for QTc correction is the Fredericia formula (QT / ∛RR).1Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study drug administration(s).sParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.hAfter signing of the ICF, but prior to initiation of study intervention, AEs related to protocol-mandated procedures and all SAEs will be reported. Following initiation of study drug, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.1Screening viral serology parameters include HAV, HCV, HEV, and HIV.1Additional samples may be collected at any time if immune complex disease is suspected.kCBP participants are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and a urine pregnancy test will be performed thereafter.Negative pregnancy test must be confirmed prior to study drug administration.1Does not need to be performed if the participant has had a FibroScan® or liver biopsy in the 12 months prior to screening. Alternatives to FibroScan®, e.g., 2D-Shear Wave Elastography, can be allowed following approval of the Sponsor.mResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.nIncludes samples for ADA and NAb, as applicable for tobevibart and elebsiran. At visits where study intervention is administered, samples should be collected prior to dosing at each indicated timepoint. Additional samples for immunogenicity analysis may be collected if a persistent drug related immunologic event is suspected. ° Samples for tobevibart PK will be collected predose.pOn Day 1, samples for elebsiran PK will be collected predose, at 1.5 hours (± 15 minutes) and 4 hours (± 15 minutes) postdose. At Week 24 and Week 48, samples for elebsiran PK will17181072933.1be collected at 1.5 hours (± 15 minutes) and 4 hours (± 15 minutes) postdose.qRefer to the SoA in Figure 20.rPROs will be collected where available and approved. PROs are to be completed on site and when possible, prior to any other study procedures or discussions with the Investigator or study staff participating in participant care or clinical evaluations.

[0022] Figures 14A-14B show the Schedule of Activities for the study intervention treatment period for participants receiving tobevibart+elebsiran (Arm 1; Screen to Week 52 to Week 240) for the clinical study in Example 3. anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; CBP = childbearing potential; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; D = Day; ECI = events of clinical interest; EOT = end of treatment; EQ-5D-5L = EuroQol 5-Dimension 5-Level; ET = early termination; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; PBMC = peripheral blood mononuclear cells; PRO = patient-reported outcome; Q4W = every 4 weeks; SoA = Schedule of Activities; TSQM 9 = treatment satisfaction questionnaire for medication; W = Week.aVisits will occur every 4 weeks (± 2 days) between Week 52 and Week 240 for tobevibart+elebsiran administration, pregnancy testing, AE and concomitant medications review and record, and laboratory ECI surveillance.bThe HDV RNA results from the Week 92 visit (or the most recently available data) will be used to assess eligibility for tobevibart+elebsiran interruption. Participants who systematically interrupt tobevibart+elebsiran will proceed to the SoA in Figures 18A-18B starting at Week 96. Participants who do not meet criteria or who were randomized to Arm 2 and switched to tobevibart+elebsiran, will continue with this SoA schedule.cIf a participant prematurely discontinues study intervention, an ET visit should be scheduled as early as possible regardless of the target visit day / window, and the participant will then follow the SoA in Figure 19 for the Safety Follow-up Period.dVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample18181072933.1collections and study drug administration(s).eParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.fAdditional samples may be collected at any time if immune complex disease is suspected.gCBP participants are required to have pregnancy tests. Negative urine pregnancy test must be confirmed prior to study drug administration.hResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.iRefer to the SoA in Figure 20.jLiver biopsy can be conducted at Week 144 or Week 192.kPROs will be collected where available and approved. PROs are to be completed on site and when possible, prior to any other study procedures or discussions with the Investigator or study staff participating in participant care or clinical evaluations.

[0023] Figures 15A-15C show the Schedule of Activities for the study intervention treatment period for participants receiving receiving bulevirtide (Arm 2; Screen to Week 48) for the clinical study in Example 3. AE = adverse event; ALT = alanine aminotransferase; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; BLV = bulevirtide; CBP = childbearing potential; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; D = Day; ECG = electrocardiogram; ECI = Events of Clinical Interest; EQ-5D-5L = EuroQol 5-Dimension 5-Level; ET = early termination; HAV = hepatitis A virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; ICF = informed consent form; IDMC = independent data monitoring committee; PBMC = peripheral blood mononuclear cells; PRO = patient-reported outcomes; SAE = serious adverse event; SoA = Schedule of Activities; TSQM-9 = treatment satisfaction questionnaire for medication; W = Week.11The screening period can be extended to 7 weeks (49 days) for participants requiring a repeat assessment due to technical issues with the samples or delays in receiving HDV RNA results.bIf a participant prematurely19181072933.1discontinues study intervention, an ET visit should be scheduled as early as possible regardless of the target visit day / window, and the participant will then follow the SoA in Figure 19 for the Safety Follow-Up Period.cAfter an IDMC recommendation has been made allowing participants to switch to tobevibart+elebsiran, participants switching to tobevibart+elebsiran will receive the first doses of tobevibart+elebsiran at Week 52 or at the earliest feasible visit after Week 52 but preferably within the next 2 scheduled study visits. Participants should continue to administer BLV until the first doses of tobevibart+elebsiran. Follow the SoA in Figures 17A-17C for the first 7 doses of tobevibart+elebsiran, then follow the SoA in Figures 14A-14B at the next scheduled visit. BLV participants must have Week 48 HDV RNA and ALT data resulted prior to switching.dTraining on self-administration will be provided to participants on Day 1 and dosing will occur on site. Sites should provide additional training during W1 for participants who need additional guidance on self-administration after the DI visit.eBLV to be dispensed every 4 w eeks during scheduled site visits, with the requirement for daily injections. Additional supply may be dispensed to ensure adequate quantity for daily dosing upon Investigator and Sponsor approval.fParticipants are required to bring back all BLV vials dispensed at the last visit(s), used and unused, and sites will perform accountability and compliance assessment.8A complete medical history will be taken at screening, including HBV and HDV genotype if available. Any changes to medical history should be reviewed and updated prior to dosing on DI.hPrior to study drug administration on Day 1, participant eligibility will be confirmed by the site.1A single 12-lead safety ECG will be recorded at screening and pre-dose (within 1 hour) and should be measured prior to any vital sign measurements or blood draws scheduled on the same assessment day, in the supine position after the participant has rested comfortably for approximately 10 minutes. The preferred method for QTc correction is the Fredericia formula (QT / ∛RR). ■> Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study drug administration(s).kParticipants will be monitored for laboratory ECI, and additional20181072933.1assessments may be performed if indicated.1After signing of the ICF, but prior to initiation of study intervention, AEs related to protocol-mandated procedures and all SAEs will be reported. Following initiation of study drug, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.mScreening viral serology parameters include HAV, HCV, HEV, and HIV.nAdditional samples may be collected at any time if immune complex disease is suspected. ° CBP participants are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and a urine pregnancy test will be performed thereafter.Negative pregnancy test must be confirmed prior to study drug administration.pDoes not need to be performed if the participant has had a FibroScan® or liver biopsy in the 12 months prior to screening. Alternatives to FibroScan®, e.g. 2D-Shear Wave Elastography, can be allowed following approval of the Sponsor.qResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.rRefer to the SoA in Figure 20.sPROs will be collected where available and approved. PROs to be completed on site and when possible, prior to any other study procedures or discussions with the Investigator or study staff participating in participant care or clinical evaluations.

[0024] Figures 16A-16C show the Schedule of Activities for the study intervention treatment period for participants receiving receiving bulevirtide (Arm 2; Week 52 to Week 240) for the clinical study in Example 3. AE = adverse event; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; BLV = bulevirtide; CBP = childbearing potential; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; D = Day; ECI = events of clinical interest; EOT = end of treatment; EQ-5D-5L = EuroQol 5-Dimension 5-Level; ET = early termination; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; PBMC = peripheral blood mononuclear cells; PRO = patient-reported outcome; Q4W = every 4 weeks; SoA =21181072933.1Schedule of Activities; TSQM-9 = treatment satisfaction questionnaire for medication; W = Week.aVisits will occur every 4 weeks (± 2 days) between Week 52 to Week 236 for BLV dispensing and compliance monitoring, pregnancy testing, AE and concomitant medications review and record, and laboratory ECI surveillance.Participants are required to bring back all BLV vials dispensed at the last visit(s), used and unused, and sites will perform accountability and compliance assessment.bIf a participant prematurely discontinues study intervention, an ET visit should be scheduled as early as possible regardless of the target visit day / window, and the participant will then follow the SoA in Figure 19 for the Safety Follow-up Period.cVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study drug administration(s).dParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.eAdditional samples may be collected at any time if immune complex disease is suspected.fCBP participants are required to have pregnancy tests. Negative urine pregnancy test must be confirmed prior to study drug administration.gResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.hRefer to the SoA in Figure 20.iLiver biopsy can be conducted at Week 144 or Week 192. J PROs will be collected where available and approved. PROs are to be completed on site and when possible, prior to any other study procedures or discussions with the Investigator or study staff participating in participant care or clinical evaluations.

[0025] Figures 17A-17C show the Schedule of Activities for bulevirtide participants switching to tobevibart+elebsiran (Switch DI to Switch Week 24 / First 7 doses of tobevibart+elebsiran) for the clinical study in Example 3. ADA = anti-drug antibodies; ALT = alanine aminotransferase; anti-HBe = hepatitis B e antigen antibody;22181072933.1anti-HBs = hepatitis B surface antigen antibody; BLV =bulevirtide; CBP = childbearing potential; CLDQ-HBV =chronic liver disease questionnaire - Hepatitis B; CPT = Child-Pugh-Turcotte; D = Day; ECI = Events of Clinical Interest; EQ-5D-5L = EuroQol 5-Dimension 5-Level; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; IDMC = independent data monitoring committee; NAb = neutralizing antibodies; PK = pharmacokinetic; PRO = patient-reported outcome; SoA = Schedule of Activities; SW =switch week; TSQM-9 = treatment satisfaction questionnaire for medication.aIf Week 240 occurs during the switch schedule shown in Figures 17A-17C. participants should complete the Week 240 visit assessments in Figures 14A-14B instead of completing the rest of the switch schedule.bAfter first 7 doses, participants should return to the SoA in Figures 14A-14B and continue the next scheduled visits every 4 weeks as per the SoA in Figures 14A-14B.cParticipants will continue to receive BLV until an IDMC recommendation is made for participants to switch to tobevibart+elebsiran. After an IDMC recommendation has been made, participants switching to tobevibart+elebsiran will receive the first doses of tobevibart+elebsiran at Week 52 or at the earliest feasible visit after Week 52 but preferably within the next 2 study visits. Participants should continue to administer BLV until the first doses of tobevibart+elebsiran. BLV participants must have the Week 48 HDV RNA and ALT data resulted prior to switching.dParticipants are required to bring back all BLV vials dispensed at the last visit(s), used and unused, and sites will perform accountability and compliance assessment.6Prior to tobevibart+elebsiran administration on Switch Day 1, switch criteria (HDV RNA and ALT results) must be confirmed.fVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections and study drug administration(s).8Participants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.hAdditional samples may be collected at any time if immune complex disease is suspected.1CBP participants are required to have pregnancy tests. Negative urine pregnancy test must be23181072933.1confirmed prior to study drug administration.jResistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.kIncludes samples for ADA and NAb, as applicable for tobevibart and elebsiran. At visits where study intervention is administered, samples should be collected prior to dosing at each indicated timepoint. Additional samples for immunogenicity analysis may be collected if a persistent drug related immunologic event is suspected.1Samples for tobevibart PK will be collected predose.mSamples for elebsiran PK will be collected at 1.5 hours (± 15 minutes) and 4 hours (± 15 minutes) postdose.nPROs will be collected where available and approved. PROs are to be completed on site and when possible, prior to any other study procedures or discussions with the Investigator or study staff participating in participant care or clinical evaluations.

[0026] Figures 18A-18B show the Schedule of Activities for Week 96 to Week 240 - Systematic Tobevibart+Elebsiran Interruption (Arm 1 only) for the clinical study in Example 3. ADA = anti-drug antibodies; AE = adverse event; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; CBP = childbearing potential; CPT = Child-Pugh-Turcotte; D = Day; ECI = events of clinical interest; ET = early termination; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic; SAE = serious adverse event; SoA = Schedule of Activities; W = Week.aParticipants who discontinue study during the treatment interruption period from Week 96 to Week 120 will have an ET visit and then be followed for an additional 24 weeks per the Safety Follow-up SoA in Figure 19. Participants who discontinue study during treatment interruption period after Week 120 will have an ET visit and do not require safety follow-up.bThe HDV RNA results from the Week 92 visit (or the most recently available data) will be used to assess eligibility for tobevibart+elebsiran interruption.cVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested24181072933.1comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections).dParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.eFollowing initiation of study drug, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.fCBP participants are required to have urine pregnancy tests for 6 months following cessation of therapy.8Resistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.hIncludes samples for ADA and neutralizing antibodies (NAb), as applicable for tobevibart and elebsiran. Additional samples for immunogenicity analysis may be collected if a persistent drug related immunologic event is suspected.1Refer to the SoA in Figure 20. ' Liver biopsy can be conducted at Week 144 or Week 192.

[0027] Figure 19 shows the Schedule of Activities for the Safety Follow-Up Period (Arms 1 and 2) for the clinical study in Example 3. ADA = anti-drug antibodies; AE = adverse event; anti-HBe = hepatitis B e antigen antibody; anti-HBs = hepatitis B surface antigen antibody; CBP = childbearing potential; CPT = Child-Pugh-Turcotte; ECI = Events of Clinical Interest; EOT = end of treatment; ET = early termination; FD = follow-up day; FW = follow-up week; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis D virus; NAb = neutralizing antibodies; PRO = patient-reported outcome; SAE = serious adverse event; SoA = schedule of activities.aFollow-up visits per this SoA to be initiated after the ET or EOT visit, for participants that received at least 1 dose of tobevibart or elebsiran.bVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital signs must be performed before blood sample collections.cParticipants will be monitored for laboratory ECI, and additional assessments may be performed if indicated.dFollowing25181072933.1initiation of study intervention, all AEs / SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study.eCBP participants are required to have urine pregnancy tests.fIncludes samples for ADA and NAb, as applicable for elebsiran and tobevibart.8Resistance surveillance sample may be used for viral genotyping. As it will not be known at the time of visit if a participant has virologic breakthrough, samples for resistance surveillance will be collected at all study visits noted in the SoA. Samples collected for resistance surveillance may be used to perform additional viral analyses, including viral sequencing.hPROs will be collected where available and approved. PROs are to be completed on site and when possible, prior to any other study procedures or discussions with the Investigator or study staff participating in participant care or clinical evaluations.

[0028] Figure 20 shows the Schedule of Activities for the Liver Biopsy substudy (Optional Substudy; Arm 1) for the clinical trial in Example 3. D = Day; HBsAg = hepatitis B surface antigen; HDV = hepatitis D virus; W = Week.aVisit can be conducted at Week 144 or Week 192.bA pretreatment liver tissue sample will be collected during the screening window or up to Week 2 of the study. If the participant has a liver biopsy in the prior 12 months and the tissue block is available for research use and deemed usable by the Sponsor, this sample can be used as the pretreatment sample.eAssessments will not be performed and laboratory samples will not be collected for Liver Biopsy Substudy if same assessments and samples were already collected on the same day for a regular study visit.dVital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 minutes. The assessments of vital signs must be performed before blood sample collections.DETAILED DESCRIPTION

[0029] The instant disclosure provides methods and compositions for use in treating hepatitis D virus (HDV) infection or a HDV-associated disease, wherein the subject is administered one or more of tobevibart, an anti-HBV antibody, and elebsiran, an anti-HBV siRNA.26181072933.1I. Glossary

[0030] The following sections provide a detailed description of combination therapies for treating HDV infection or a HDV-associated disease. Prior to setting forth this disclosure in more detail, it may be helpful to an understanding thereof to provide definitions of certain terms to be used herein. Additional definitions are set forth throughout this disclosure.

[0031] In the present description, the term "about" means + 20% (plus or minus 20%) of the indicated range, value, or structure, unless otherwise indicated.

[0032] The term "comprise" (and similar terms such as "comprising of and "comprised of) means the presence of the stated features, integers, steps, or components as referred to in the claims, but that it does not preclude the presence or addition of one or more other features, integers, steps, components, or groups thereof. The term "consisting essentially of limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention.

[0033] It should be understood that the terms "a" and "an" as used herein refer to "one or more" of the enumerated components. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives, and may be used synonymously with "and / or". As used herein, the terms "include" and "have" are used synonymously, which terms and variants thereof are intended to be construed as non-limiting or open-ended.

[0034] The word "substantially" does not exclude "completely"; e.g, a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from definitions provided herein.

[0035] The term "disease" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disorder" and "condition" (as in "medical condition"), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by 27181072933.1distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0036] As used herein, the terms "peptide", "polypeptide", and "protein" and variations of these terms refer to a molecule, in particular a peptide, oligopeptide, polypeptide, or protein including fusion protein, respectively, comprising at least two amino acids joined to each other by a normal peptide bond, or by a modified peptide bond, such as for example in the cases of isosteric peptides. For example, a peptide, polypeptide, or protein may be composed of amino acids selected from the 20 amino acids defined by the genetic code, linked to each other by a normal peptide bond ("classical" polypeptide). A peptide, polypeptide, or protein can be composed of L-amino acids and / or D-amino acids. In particular, the terms "peptide", "polypeptide", and "protein" also include "peptidomimetics," which are defined as peptide analogs containing non-peptidic structural elements, which peptides are capable of mimicking or antagonizing the biological action(s) of a natural parent peptide. A peptidomimetic lacks classical peptide characteristics such as enzymatically scissile peptide bonds. In particular, a peptide, polypeptide, or protein may comprise amino acids other than the 20 amino acids defined by the genetic code in addition to these amino acids, or it can be composed of amino acids other than the 20 amino acids defined by the genetic code. In particular, a peptide, polypeptide, or protein in the context of the present disclosure can equally be composed of amino acids modified by natural processes, such as post-translational maturation processes or by chemical processes, which are well known to a person skilled in the art. Such modifications are fully detailed in the literature. These modifications can appear anywhere in the polypeptide: in the peptide skeleton, in the amino acid chain, or even at the carboxy- or amino-terminal ends. In particular, a peptide or polypeptide can be branched following an ubiquitination or be cyclic with or w ithout branching. This type of modification can be the result of natural or synthetic post-translational processes that are well known to a person skilled in the art. The terms "peptide", "polypeptide", or "protein" in the context of the present disclosure in particular also include modified peptides, polypeptides, and proteins. For example, peptide, polypeptide, or protein modifications can include acetylation, acylation, ADP-28181072933.1ribosylation, amidation, covalent fixation of a nucleotide or of a nucleotide derivative, covalent fixation of a lipid or of a lipidic derivative, the covalent fixation of a phosphatidylinositol, covalent or non-covalent cross- linking, cyclization, disulfide bond formation, demethylation, glycosylation including pegylation, hydroxylation, iodization, methylation, myristoylation, oxidation, proteolytic processes, phosphorylation, prenylation, racemization, seneloylation, sulfatation, amino acid addition such as arginylation, or ubiquitination. Such modifications are fully detailed in the literature (Proteins Structure and Molecular Properties, 2nd Ed., T. E. Creighton, New York (1993); Post-translational Covalent Modifications of Proteins, B. C. Johnson, Ed., Academic Press, New York (1983); Seifter et al., Analysis for protein modifications and nonprotein cofactors, Meth. Enzymol. 1990, 182:626-46; and Rattan et al., Protein Synthesis: Post-translational Modifications and Aging, Ann NY Acad Sci 1992, 663:48-62). Accordingly, the terms "peptide", "polypeptide", and "protein" include for example lipopeptides, lipoproteins, glycopeptides, glycoproteins, and the like.

[0037] As used herein a "(poly)peptide" comprises a single chain of amino acid monomers linked by peptide bonds as explained above. A "protein", as used herein, comprises one or more, e.g., 1. 2, 3, 4, 5, 6, 7, 8. 9 or 10 (poly)peptides, i.e., one or more chains of amino acid monomers linked by peptide bonds as explained above. In particular embodiments, a protein according to the present disclosure comprises 1, 2, 3, or 4 polypeptides.

[0038] The term "recombinant", as used herein (e.g., a recombinant antibody, a recombinant protein, a recombinant nucleic acid, etc.), refers to any molecule (antibody, protein, nucleic acid, siRNA, etc.) that is prepared, expressed, created, or isolated by recombinant means, and which is not naturally occurring. As used herein, the terms "nucleic acid", "nucleic acid molecule," and "polynucleotide" are used interchangeably and are intended to include DNA molecules and RNA molecules. A nucleic acid molecule may be single-stranded or double-stranded. In particular embodiments, the nucleic acid molecule is double-stranded RNA.29181072933.1

[0039] As used herein, the terms "cell," "cell line," and "cell culture" are used interchangeably and all such designations include progeny. Thus, the words "transformants" and "transformed cells" include the primary subject cell and cultures derived therefrom without regard for the number of transfers. It is also understood that all progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Variant progeny that have the same function or biological activity as screened for in the originally transformed cell are included. Where distinct designations are intended, it will be clear from the context.

[0040] As used herein, the term "sequence variant" refers to any sequence having one or more alterations in comparison to a reference sequence, whereby a reference sequence is any of the sequences listed in the sequence listing, i.e., SEQ ID NO:1 to SEQ ID NO:19. Thus, the term "sequence variant" includes nucleotide sequence variants and amino acid sequence variants. For a sequence variant in the context of a nucleotide sequence, the reference sequence is also a nucleotide sequence, whereas for a sequence variant in the context of an amino acid sequence, the reference sequence is also an amino acid sequence. A "sequence variant" as used herein is at least 80%, at least 85 %, at least 90%, at least 95%, at least 98%, or at least 99% identical to the reference sequence. Sequence identity is usually calculated with regard to the full length of the reference sequence (i.e., the sequence recited in the application), unless otherwise specified. Percentage identity, as referred to herein, can be determined, for example, using BLAST using the default parameters specified by the NCBI (the National Center for Biotechnology Information; www.ncbi.nlm.nih.gov / ) [Blosum 62 matrix; gap open penalty=11 and gap extension penalty=1], A "sequence variant" in the context of a nucleic acid (nucleotide) sequence has an altered sequence in which one or more of the nucleotides in the reference sequence is deleted, or substituted, or one or more nucleotides are inserted into the sequence of the reference nucleotide sequence. Nucleotides are referred to herein by the standard one-letter designation (A, C, G, or T). Due to the degeneracy of the genetic code, a "sequence variant" of a nucleotide sequence can either result in a change in the respective reference amino acid sequence, i.e., in an amino acid "sequence variant" or not. In certain embodiments, the nucleotide30181072933.1sequence variants are variants that do not result in amino acid sequence variants (i.e., silent mutations). However, nucleotide sequence variants leading to "non-silent" mutations are also within the scope, in particular such nucleotide sequence variants, which result in an amino acid sequence, which is at least 80%, at least 85 %, at least 90%, at least 95%, at least 98%, or at least 99% identical to the reference amino acid sequence. A "sequence variant" in the context of an amino acid sequence has an altered sequence in which one or more of the amino acids is deleted, substituted or inserted in comparison to the reference amino acid sequence. As a result of the alterations, such a sequence variant has an amino acid sequence which is at least 80%. at least 85 %, at least 90%, at least 95%, at least 98%, or at least 99% identical to the reference amino acid sequence. For example, per 100 amino acids of the reference sequence a variant sequence having no more than 10 alterations, i.e., any combination of deletions, insertions, or substitutions, is "at least 90% identical" to the reference sequence.

[0041] While it is possible to have non-conservative amino acid substitutions, in certain embodiments, the substitutions are conservative amino acid substitutions, in which the substituted amino acid has similar structural or chemical properties with the corresponding amino acid in the reference sequence. By way of example, conservative amino acid substitutions involve substitution of one aliphatic or hydrophobic amino acids, e.g, alanine, valine, leucine, and isoleucine, with another; substitution of one hydoxyl-containing amino acid, e.g., serine and threonine, with another; substitution of one acidic residue, e.g., glutamic acid or aspartic acid, with another; replacement of one amide-containing residue, e.g., asparagine and glutamine, with another; replacement of one aromatic residue, e.g., phenylalanine and tyrosine, with another; replacement of one basic residue, e.g., lysine, arginine, and histidine, with another; and replacement of one small amino acid, e.g, alanine, serine, threonine, methionine, and glycine, with another.

[0042] Amino acid sequence insertions include amino- and / or carboxyl -terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include the fusion to the N- or C-terminus of an amino acid sequence to a reporter molecule or an enzyme.31181072933.1

[0043] Unless otherwise stated, alterations in the sequence variants do not abolish the functionality of the respective reference sequence, for example, in the present case, the functionality of a sequence of an anti-HBV antibody or an siRNA to sufficiently neutralize infection of HBV or reduce HBV protein expression, respectively. Guidance in determining which nucleotides and amino acid residues, respectively, may be substituted, inserted, or deleted without abolishing such functionality can be found by using computer programs well known in the art.

[0044] As used herein, a nucleic acid sequence or an amino acid sequence "derived from" a designated nucleic acid, peptide, polypeptide, or protein refers to the origin of the nucleic acid, peptide, polypeptide, or protein. In some embodiments, the nucleic acid sequence or amino acid sequence which is derived from a particular sequence has an amino acid sequence that is essentially identical to that sequence or a portion thereof, from which it is derived, whereby "essentially identical" includes sequence variants as defined above. In certain embodiments, the nucleic acid sequence or amino acid sequence which is derived from a particular peptide or protein is derived from the corresponding domain in the particular peptide or protein. Thereby, "corresponding" refers in particular to the same functionality. For example, an "extracellular domain" corresponds to another "extracellular domain" (of another protein), or a "transmembrane domain" corresponds to another "transmembrane domain" (of another protein). " Corresponding" parts of peptides, proteins, and nucleic acids are thus identifiable to one of ordinary skill in the art. Likewise, sequences "derived from" other sequence are usually identifiable to one of ordinary skill in the art as having its origin in the sequence.

[0045] In some embodiments, a nucleic acid sequence or an amino acid sequence derived from another nucleic acid, peptide, polypeptide, or protein may be identical to the starting nucleic acid, peptide, polypeptide, or protein (from which it is derived). However, a nucleic acid sequence or an amino acid sequence derived from another nucleic acid, peptide, polypeptide, or protein may also have one or more mutations relative to the starting nucleic acid, peptide, polypeptide, or protein (from which it is derived), in particular a nucleic acid sequence or an amino acid sequence32181072933.1derived from another nucleic acid, peptide, polypeptide, or protein may be a functional sequence variant as described above of the starting nucleic acid, peptide, polypeptide, or protein (from which it is derived). For example, in a peptide / protein one or more amino acid residues may be substituted with other amino acid residues or one or more amino acid residue insertions or deletions may occur.

[0046] As used herein, the term "mutation" relates to a change in the nucleic acid sequence and / or in the amino acid sequence in comparison to a reference sequence, e.g., a corresponding genomic sequence. A mutation, e.g, in comparison to a genomic sequence, may be, for example, a (naturally occurring) somatic mutation, a spontaneous mutation, an induced mutation, e.g., induced by enzymes, chemicals, or radiation, or a mutation obtained by site-directed mutagenesis (molecular biology methods for making specific and intentional changes in the nucleic acid sequence and / or in the amino acid sequence). Thus, the terms "mutation" or "mutating" shall be understood to also include physically making a mutation, e.g., in a nucleic acid sequence or in an amino acid sequence. A mutation includes substitution, deletion, and insertion of one or more nucleotides or amino acids as well as inversion of several successive nucleotides or amino acids. To achieve a mutation in an amino acid sequence, a mutation may be introduced into the nucleotide sequence encoding said amino acid sequence in order to express a (recombinant) mutated polypeptide. A mutation may be achieved, e.g, by altering, e.g., by site-directed mutagenesis, a codon of a nucleic acid molecule encoding one amino acid to result in a codon encoding a different amino acid, or by synthesizing a sequence variant, e.g, by knowing the nucleotide sequence of a nucleic acid molecule encoding a polypeptide and by designing the synthesis of a nucleic acid molecule comprising a nucleotide sequence encoding a variant of the polypeptide without the need for mutating one or more nucleotides of a nucleic acid molecule.

[0047] As used herein, the term "coding sequence" is intended to refer to a polynucleotide molecule, which encodes the amino acid sequence of a protein product. The boundaries of the coding sequence are generally determined by an open reading frame, which usually begins with an ATG start codon.33181072933.1

[0048] The term "expression" as used herein refers to any step involved in the production of the polypeptide, including transcription, post-transcriptional modification, translation, post-translational modification, secretion, or the like.

[0049] The term "vaccine" as used herein is typically understood to be a prophylactic or therapeutic material providing at least one antigen or immunogen, including viral vector vaccines that include nucleic acids encoding the antigen(s) or immunogen(s). The antigen or immunogen may be derived from any material that is suitable for vaccination. For example, the antigen or immunogen may be derived from a pathogen, such as from bacteria or virus particles, etc., or from a tumor or cancerous tissue. The antigen or immunogen stimulates the body's adaptive immune system to provide an adaptive immune response. In particular, an "antigen" or an "immunogen" refers typically to a substance which may be recognized by the immune system (e.g. the adaptive immune system), and which is capable of triggering an antigen-specific immune response, e.g., by formation of antibodies and / or antigen-specific T cells as part of an adaptive immune response. Typically, an antigen may be or may comprise a peptide or protein that may be presented by the MHC to T-cells.

[0050] As used herein, " Hepatitis B virus," used interchangeably with the term " HBV" refers to the well-known non-cytopathic, liver-tropic DNA virus belonging to the Hepadnaviridae family. The HBV genome is partially double-stranded, circular DNA with four overlapping reading frames (that may be referred to herein as "genes," "open reading frames," or "transcripts"): C, X. P, and S. The core protein is coded for by gene C (HBcAg). Hepatitis B e antigen (HBeAg) is produced by proteolytic processing of the pre-core (pre-C) protein. The DNA polymerase is encoded by gene P. Gene S is the gene that codes for the surface antigens (HBsAg). The HBsAg gene is one long open reading frame which contains three in frame "start" (ATG) codons resulting in polypeptides of three different sizes called large, middle, and small S antigens, pre-S1 + pre-S2 + S, pre-S2 + S, or S. Surface antigens, in addition to decorating the envelope of HBV, are also part of subviral particles, which are produced at large excess as compared to virion particles, and play a role in immune tolerance and in sequestering anti-HBsAg antibodies, thereby allowing for infectious particles to escape immune34181072933.1detection. The protein coded for by gene X plays a role in transcriptional transactivation and replication and is associated with the development of liver cancer.

[0051] Nine genotypes of HBV. designated A to I, have been determined, and an additional genotype J has been proposed, each having a distinct geographical distribution (Velkov S et al., The Global Hepatitis B Virus Genotype Distribution Approximated from Available Genotyping Data, Genes 2018. 9(10):495). The term " HBV" includes any of the genotypes of HBV (A to J). The complete coding sequence of the reference sequence of the HBV genome may be found in for example, GenBank Accession Nos. GI:21326584 and GI:3582357. Amino acid sequences for the C, X, P, and S proteins can be found at, for example, NCBI Accession numbers YP_009173857.1 (C protein); YP_009173867.1 and BAA32912.1 (X protein);YP_009173866.1 and BAA32913.1 (P protein); and YP 009173869.1,YP_009173870.1, YP_009173871.1, and BAA32914.1 (S protein). Additional examples of HBV messenger RNA (mRNA) sequences are available using publicly available databases, e.g., GenBank, UniProt, and OMIM. The International Repository for Hepatitis B Virus Strain Data can be accessed at www.hpa-bioinformatics.org.uk / HepSEQ / main.php. The term " HBV," as used herein, also refers to naturally occurring DNA sequence variations of the HBV genome, i.e., genotypes A-J and variants thereof.

[0052] In some embodiments, the present disclosure provides combination therapy to treat HBV that includes an anti-HBV siRNA. siRNA mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway, thereby effecting inhibition of gene expression. This process is frequently termed " RNA interference" (RNAi). Without wishing to be bound to a particular theory, long doublestranded RNA (dsRNA) introduced into plants and invertebrate cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al., Genes Dev. 2001, 15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair siRNAs with characteristic two base 3' overhangs (Bernstein et al.. Nature 2001.409:363). The siRNAs are then incorporated into RISC where one or more helicases unwind the siRNA duplex, enabling the complementary" antisense strand to guide target35181072933.1recognition (Nykanen et al., Cell 2001 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within RISC cleaves the target to induce silencing (Elbashir et al.. Genes Dev. 2001, 15:188).

[0053] The terms "silence," "inhibit the expression of," "down-regulate the expression of," "suppress the expression of," and the like, in so far as they refer to an HBV gene, herein refer to the at least partial reduction of the expression of an HBV gene, as manifested by a reduction of the amount of HBV mRNA which can be isolated from or detected in a first cell or group of cells in which an HBV gene is transcribed and which has or have been treated with an inhibitor of HBV gene expression, such that the expression of the HBV gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). The degree of inhibition can be measured, by example, as the difference between the degree of mRNA expression in a control cell minus the degree of mRNA expression in a treated cell. Alternatively, the degree of inhibition can be given in terms of a reduction of a parameter that is functionally linked to HBV gene expression, e.g, the amount of protein encoded by an HBV gene, or the number of cells displaying a certain phenotype, e.g, an HBV infection phenotype. In principle, HBV gene silencing can be determined in any cell expressing the HBV gene, e.g., an HBV-infected cell or a cell engineered to express the HBV gene, and by any appropriate assay.

[0054] The level of HBV RNA that is expressed by a cell or group of cells, or the level of circulating HBV RNA, may be determined using any method known in the art for assessing mRNA expression, such as the rtPCR method provided in Example 2 of International Application Publication No. WO 2016 / 077321 Al and U. S. Patent Application Publication No. US2017 / 0349900A1. which methods are incorporated herein by reference. In some embodiments, the level of expression of an HBV gene (e.g, total HBV RNA, an HBV transcript, e.g., HBV 3.5 kb transcript) in a sample is determined by detecting a transcribed polynucleotide, or portion thereof, e.g. RNA of the HBV gene. RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol / guanidine isothiocyanate extraction (RNAzol36181072933.1B; Biogenesis), RNeasy RNA preparation kits (Qiagen®), or PAXgene (PreAnalytix, Switzerland). Typical assay formats utilizing ribonucleic acid hybridization include nuclear run-on assays, RT-PCR, RNase protection assays (Melton DA et al., Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter, Nuc. Acids Res. 1984, 12:7035-56), northern blotting, in situ hybridization, and microarray analysis. Circulating HBV mRNA may be detected using methods the described in International Application Publication No. WO 2012 / 177906A1 and U. S. Patent Application Publication No. US2014 / 0275211A1, which methods are incorporated herein by reference.

[0055] As used herein, "target sequence" refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of an HBV gene, including mRNA that is a product of RNA processing of a primary transcription product. The target portion of the sequence will be at least long enough to serve as a substrate for RNAi-directed cleavage at or near that portion. For example, the target sequence will generally be from 9-36 nucleotides in length, e.g, 15-30 nucleotides in length, including all sub-ranges there between. As non-limiting examples, a target sequence can be from 15-30 nucleotides, 15-26 nucleotides, 15-23 nucleotides, 15-22 nucleotides, 15-21 nucleotides, 15- 20 nucleotides, 15-19 nucleotides, 15-18 nucleotides, 15-17 nucleotides, 18-30 nucleotides, 18-26 nucleotides, 18-23 nucleotides, 18-22 nucleotides, 18-21 nucleotides, 18-20 nucleotides, 19-30 nucleotides, 19-26 nucleotides, 19-23 nucleotides, 19-22 nucleotides, 19- 21 nucleotides, 19-20 nucleotides, 20-30 nucleotides, 20-26 nucleotides, 20-25 nucleotides, 20- 24 nucleotides, 20-23 nucleotides, 20-22 nucleotides, 20-21 nucleotides, 21-30 nucleotides, 21-26 nucleotides, 21-25 nucleotides, 21-24 nucleotides, 21-23 nucleotides, or 21- 22 nucleotides.

[0056] As used herein, the term "strand comprising a sequence" refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature.

[0057] As used herein, and unless otherwise indicated, the term "complementary," when used to describe a first nucleotide sequence in relation to a37181072933.1second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50°C or 70°C for 12-16 hours followed by washing. Other conditions, such as physiologically relevant conditions as can be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides.

[0058] Complementary sequences within an siRNA as described herein include base-pairing of the oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as "fully complementary " with respect to each other herein. However, where a first sequence is referred to as "substantially complementary" with respect to a second sequence herein, the two sequences can be fully complementary, or they can form one or more, but generally not more than 5, 4, 3, or 2 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RISC pathway. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, an siRNA comprising one oligonucleotide 21 nucleotides in length, and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, can yet be referred to as "fully complementary" for the purposes described herein.

[0059] " Complementary" sequences, as used herein, can also include, or be formed entirely from non-Watson-Crick base pairs and / or base pairs formed from non-38181072933.1natural and modified nucleotides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G: U Wobble or Hoogstein base pairing.

[0060] The terms "complementary," "fully complementary," and "substantially complementary" herein can be used with respect to the base matching between the sense strand and the antisense strand of an siRNA, or between the antisense strand of an siRNA agent and a target sequence, as will be understood from the context of their use.

[0061] As used herein, a polynucleotide that is "substantially complementary " to at least part of a mRNA refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g, an mRNA encoding an HBV protein). For example, a polynucleotide is complementary to at least a part of an HBV mRNA if the sequence is substantially complementary to a noninterrupted portion of the HBV mRNA.

[0062] The term "siRNA," as used herein, refers to an RNA interference molecule that includes an RNA molecule or complex of molecules having a hybridized duplex region that comprises two anti-parallel and substantially complementary nucleic acid strands, which will be referred to as having "sense" and "antisense" orientations with respect to a target RNA. The duplex region can be of any length that permits specific degradation of a desired target RNA through a RISC pathway, but will typically range from 9 to 36 base pairs in length, e.g., 15-30 base pairs in length.Considering a duplex between 9 and 36 base pairs, the duplex can be any length in this range, for example, 9, 10, 11, 12, 13, 14, 15. 16. 17. 18. 19. 20, 21. 22. 23. 24. 25. 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 and any sub-range there between, including, but not limited to 15-30 base pairs, 15-26 base pairs, 15-23 base pairs, 15-22 base pairs, 15-21 base pairs, 15-20 base pairs, 15-19 base pairs, 15-18 base pairs, 15- 17 base pairs.18-30 base pairs, 18-26 base pairs, 18-23 base pairs, 18-22 base pairs, 18-21 base pairs, 18-20 base pairs, 19-30 base pairs, 19-26 base pairs, 19-23 base pairs, 19-22 base pairs, 19-21 base pairs. 19-20 base pairs. 20-30 base pairs, 20-26 base pairs, 20-25 base pairs, 20-24 base pairs, 20-23 base pairs, 20-22 base pairs, 20-21 base pairs, 21-30 base pairs, 21-26 base pairs, 21-25 base pairs, 21-24 base pairs, 21-23 base pairs, and 21-22 base39181072933.1pairs. siRNAs generated in the cell by processing with Dicer and similar enzymes are generally in the range of 19-22 base pairs in length.

[0063] One strand of the duplex region of an siRNA comprises a sequence that is substantially complementary to a region of a target RNA. The two strands forming the duplex structure can be from a single RNA molecule having at least one self-complementary region, or can be formed from two or more separate RNA molecules. Where the duplex region is formed from two strands of a single molecule, the molecule can have a duplex region separated by a single stranded chain of nucleotides (herein referred to as a "hairpin loop") between the 3'-end of one strand and the 5'-end of the respective other strand forming the duplex structure. The hairpin loop can comprise at least one unpaired nucleotide; in some embodiments the hairpin loop can comprise at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides. Where the two substantially complementary strands of an siRNA are comprised by separate RNA molecules, those molecules need not, but can be covalently connected. Where the two strands are connected covalently by means other than a hairpin loop, the connecting structure is referred to as a "linker."

[0064] An siRNA as described herein can be synthesized by standard methods known in the art, e.g, by use of an automated DNA synthesizer, such as are commercially available from, for example, Biosearch, Applied Biosystems, Inc.

[0065] The term "antisense strand" or "guide strand" refers to the strand of an siRNA that includes a region that is substantially complementary to a target sequence. As used herein, the term "region of complementarity" refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches can be in the internal or terminal regions of the molecule. Generally, the most tolerated mismatches are in the terminal regions, e.g, within 5, 4. 3, or 2 nucleotides of the 5' and / or 3' terminus.40181072933.1

[0066] The term "sense strand" or "passenger strand" as used herein, refers to the strand of an siRNA that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein.

[0067] The term " RNA molecule" or "ribonucleic acid molecule" encompasses not only RNA molecules as expressed or found in nature, but also analogs and derivatives of RNA comprising one or more ribonucleotide / ribonucleoside analogs or derivatives as described herein or as known in the art. Strictly speaking, a "ribonucleoside" includes a nucleoside base and a ribose sugar, and a "ribonucleotide" is a ribonucleoside with one. two or three phosphate moieties. However, the terms "ribonucleoside" and "ribonucleotide" can be considered to be equivalent as used herein. The RNA can be modified in the nucleobase structure or in the ribose-phosphate backbone structure, e.g, as described in greater detail below. However. siRNA molecules comprising ribonucleoside analogs or derivatives retain the ability to form a duplex. As non-limiting examples, an RNA molecule can also include at least one modified ribonucleoside including but not limited to a 2'-O-methyl modified nucleoside, a nucleoside comprising a 5' phosphorothioate group, a terminal nucleoside linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a locked nucleoside, an abasic nucleoside, a 2'-deoxy-2'-fluoro modified nucleoside, a 2'-amino-modified nucleoside, 2'-alkyl-modified nucleoside, morpholino nucleoside, a phosphoramidate, or a non-natural base comprising nucleoside, or any combination thereof. In another example, an RNA molecule can comprise at least two modified ribonucleosides, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, or more, up to the entire length of the siRNA molecule. The modifications need not be the same for each of such a plurality of modified ribonucleosides in an RNA molecule. In some embodiments, a modified ribonucleoside includes a deoxyribonucleoside. For example, an siRNA can comprise one or more deoxynucleosides, including, for example, a deoxynucleoside overhang(s), or one or more deoxynucleosides within the double-stranded portion of an siRNA. However, the term "siRNA" as used herein does not include a fully DNA molecule.41181072933.1

[0068] As used herein, the term "nucleotide overhang" refers to at least one unpaired nucleotide that protrudes from the duplex structure of an siRNA. For example, when a 3'-end of one strand of an siRNA extends beyond the 5'-end of the other strand, or vice versa, there is a nucleotide overhang. An siRNA can comprise an overhang of at least one nucleotide; alternatively the overhang can comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides, or more. A nucleotide overhang can comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide / nucleoside. The overhang(s) can be on the sense strand, the antisense strand, or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5' end, 3' end, or both ends of either an antisense or sense strand of an siRNA.

[0069] The terms "blunt" or "blunt ended" as used herein in reference to an siRNA mean that there are no unpaired nucleotides or nucleotide analogs at a given terminal end of an siRNA, i. e., no nucleotide overhang. One or both ends of an siRNA can be blunt. Where both ends of an siRNA are blunt, the siRNA is said to be "blunt ended." A "blunt ended" siRNA is an siRNA that is blunt at both ends, i.e., has no nucleotide overhang at either end of the molecule. Often such a molecule will be double-stranded over its entire length.

[0070] In some embodiments, the present disclosure provides combination therapy to treat HBV that includes an anti-HBV antibody. In certain embodiments, the anti-HBV antibody or an antigen binding fragment thereof binds to the antigenic loop region of HBsAg and neutralizes infection with hepatitis B virus. In certain embodiments, the anti-HBV antibody or an antigen binding fragment thereof binds to the antigenic loop region of HBsAg and neutralizes infection with hepatitis D virus.

[0071] As used herein, the term "antibody" encompasses various forms of antibodies including, without being limited to, whole antibodies, antibody fragments, antigen binding fragments, human antibodies, chimeric antibodies, humanized antibodies, recombinant antibodies, and genetically engineered antibodies (variant or mutant antibodies) as long as the characteristic properties of the antibody are retained. In some embodiments, the antibodies are human antibodies and / or monoclonal42181072933.1antibodies. In particular embodiments, the antibodies are human monoclonal antibodies. In certain particular embodiments, the antibodies are recombinant human monoclonal antibodies. As used herein, the terms "antigen binding fragment," "fragment," and "antibody fragment" are used interchangeably to refer to any fragment of an antibody of the combination therapy that retains the antigen-binding activity' of the antibody.Examples of antibody fragments include, but are not limited to. a single chain antibody, Fab, Fab', F(ab')2, Fv, or scFv. Further, the term "antibody" as used herein includes both antibodies and antigen binding fragments thereof.

[0072] As used herein, a "neutralizing antibody" is one that can neutralize, z.e., prevent, inhibit, reduce, impede, or interfere with, the ability of a pathogen to initiate and / or perpetuate an infection in a host. The terms "neutralizing antibody" and "an antibody that neutralizes" or "antibodies that neutralize" are used interchangeably herein. These antibodies can be used alone, or in combination, as prophylactic or therapeutic agents upon appropriate formulation, in association with active vaccination, as a diagnostic tool, or as a production tool as described herein.

[0073] Human antibodies are well-known in the state of the art (van Dijk MA and van de Winkel JC, Curr. Opin. Chem. Biol. 2001, 5:368-74). Human antibodies can also be produced in transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire or a selection of human antibodies in the absence of endogenous immunoglobulin production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge (see, e.g., Jakobovits A et al, Proc. Natl. Acad. Sci. USA 1993, 90:2551-55; Jakobovits A. et al, Nature 1993, 362:255-258; Bruggemann M. et al, Year Immunol. 1993, 7:3340). Human antibodies can also be produced in phage display libraries (Hoogenboom HR and Winter G. Mol. Biol. 1992, 227:381-88; Marks JD et al, Mol Biol 1991, 222:581-97). The techniques of Cole et al. and Boemer et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boemer P et al., Immunol. 1991, 147:86-95). In some embodiments, human monoclonal antibodies are prepared by using improved EBV-B cell immortalization as43181072933.1described in Traggiai E et al. (Nat Med. 2004, 10(8): 871-5). The term "human antibody" as used herein also comprises such antibodies that are modified, e.g.. in the variable region, to generate properties as described herein.

[0074] Antibodies of the combination therapy can be of any isotype (e.g., IgA, IgG, IgM, i.e., a K, y, or p heavy chain), but in certain particular embodiments, the antibodies are IgG. Within the IgG isotype, antibodies may be IgGl, IgG2. IgG3, or IgG4 subclass. In particular embodiments, the antibodies are IgGl. Antibodies of the combination therapy may have a K or a light chain. HBsAg-specific antibodies of the IgG-type may advantageously also block the release of HBV and HBsAg from infected cells, based on antigen-independent uptake of IgG through FcRN-IgG receptors into hepatocytes. Therefore, HBsAg-specific antibodies of the IgG-type can bind intracellularly and thereby block the release of HBV virions and HBsAg.

[0075] As used herein, the term "variable region" (variable region of a light chain (VL), variable region of a heavy chain (VH)) denotes the portion of an antibody light chain (LC) or heavy chain (HC) (typically around the 105-120 amino-terminal amino acids of a mature antibody heavy chain or light chain) that comprises complementarity' determining regions (" CDRs") and framework regions (" FRs"), and that is involved directly in binding the antibody to the antigen. The terms "complementarity determining region," and " CDR," are synonymous with "hypervariable region" or " HVR," and are known in the art to refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each variable region of an immunoglobulin binding protein; e.g., for antibodies, the VH and VL regions generally comprise six CDRs (CDRH1, CDRH2, CDRH3; CDRL1, CDRL2, CDRL3). Immunoglobulin sequences can be aligned to a numbering scheme e.g., Kabat, EU, International Immunogenetics Information System (IMGT) and Aho), which can allow equivalent residue positions to be annotated and for different molecules to be compared using Antigen receptor Numbering And Receptor Classification (ANARCI) software tool (Bioinformatics 2016, 15:298-300). It will be understood that in certain embodiments, an antibody or antigen binding fragment of the44181072933.1present disclosure can comprise all or part of a heavy chain (HC), a light chain (LC), or both. For example, a full-length intact IgG antibody monomer typically includes a VH, a CHI. a CH2. a CH3. a VL. and a CL.

[0076] In certain embodiments, the anti-HBV antibodies of the combination therapy, according to the present disclosure, or the antigen binding fragment thereof, is a purified antibody, a single chain antibody, a Fab, a Fab', a F(ab')2, a Fv, or an scFv. The antibodies of the combination therapy may thus be human antibodies, monoclonal antibodies, human monoclonal antibodies, recombinant antibodies, and / or purified antibodies. The present disclosure also provides fragments of the antibodies, particularly fragments that retain the antigen-binding activity of the antibodies. Such fragments include, but are not limited to, single chain antibodies, Fab, Fab', F(ab')2, Fv, or scFv. Although in some places, the present disclosure may refer explicitly to antigen binding fragment(s), antibody fragment(s), variant(s) and / or derivative(s) of antibodies, as used herein the term "antibody" or "antibody of the combination therapy" includes all categories of antibodies, namely, antigen binding fragment(s), antibody fragment(s), variant(s), and derivative(s) of antibodies.

[0077] Fragments of the antibodies can be obtained from the antibodies by methods that include digestion with enzymes, such as pepsin or papain, and / or by cleavage of disulfide bonds by chemical reduction. Alternatively, fragments of the antibodies can be obtained by cloning and expression of part of the sequences of the heavy or light chains. The present disclosure also encompasses single-chain Fv fragments (scFv) derived from the heavy and light chains of an antibody of the disclosure. For example, the disclosure includes a scFv comprising the CDRs from an antibody of the disclosure. Also included are heavy or light chain monomers and dimers, single domain heavy chain antibodies, single domain light chain antibodies, as well as single chain antibodies, e.g., single chain Fv in which the heavy and light chain variable domains are joined by a peptide linker.

[0078] Antibody fragments of the present disclosure may impart monovalent or multivalent interactions and be contained in a variety of structures as described above. For instance, scFv molecules may be synthesized to create a trivalent "triabody" or a45181072933.1tetravalent "tetrabody." The scFv molecules may include a domain of the Fc region resulting in bivalent minibodies. In addition, the sequences of the antibody / antibody fragment may be a component of a multispecific molecule in which the sequences target the epitopes as described herein, and other regions of the multispecific molecule bind to other targets. Exemplary multispecific molecules include, but are not limited to, bispecific Fab2, trispecific Fab3, bispecific scFv, and diabodies (Holliger and Hudson. Nature Biotechnology 2005, 9:1126-36).

[0079] Antibodies according to the present disclosure may be provided in purified form. Typically, the antibody will be present in a composition that is substantially free of other polypeptides e.g., where less than 90% (by weight), usually less than 60% and more usually less than 50% of the composition is made up of other polypeptides.

[0080] Antibodies and antigen binding fragments of the present disclosure may, in embodiments, be multispecific (e.g., bispecific, trispecific, tetraspecific, or the like), and may be provided in any multispecific format, as disclosed herein. In certain embodiments, an antibody or antigen-binding fragment of the present disclosure is a multispecific antibody, such as a bispecific or trispecific antibody. Formats for bispecific antibodies are disclosed in, for example, Spiess et al. (Mol. Immunol. 2015, 67(2):95), and Brinkmann and Kontermann (mAbs 2017, 9(2): 182-212), which bispecific formats and methods of making the same are incorporated herein by reference and include, for example, Bispecific T cell Engagers (BiTEs), DARTs, Knobs-Into-Holes (KIH) assemblies, scFv-CH3-KIH assemblies, KIH Common Light-Chain antibodies, TandAbs, Triple Bodies, TriBi Minibodies, Fab-scFv, scFv-CH-CL-scFv, F(ab')2-scFv2, tetravalent HCabs, Intrabodies, CrossMabs, Dual Action Fabs (DAFs) (two-in-one or four-in-one). DutaMabs. DT-IgG, Charge Pairs. Fab-arm Exchange, SEEDbodies, Triomabs, LUZ-Y assemblies, Fcabs, KX-bodies, orthogonal Fabs, DVD-IgGs, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L, H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V. V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, and DVI-IgG (four-in-one). A bispecific or multispecific antibody may comprise a HBV- and / or HDV-specific binding domain of the instant disclosure in46181072933.1combination with another such binding domain of the instant disclosure, or in combination with a different binding domain that specifically binds to HBV and / or HDV (e.g., at a same or a different epitope), or with a binding domain that specifically binds to a different antigen.II. siRNA targeting HBV

[0081] In some embodiments, the present disclosure provides methods of treatment involving administering elebsiran, an siRNA that targets HBV mRNA.a. Elebsiran

[0082] Elebsiran is a synthetic, chemically modified siRNA targeting HBV RNA with a covalently attached tnantennary N-acetyl-galactosamine (GalNAc) ligand that allows for specific uptake by hepatocytes. Elebsiran targets mRNA encoded by a region of the HBV genome that is common to all HBV viral transcripts and is pharmacologically active against HBV genotypes A through J. In preclinical models, elebsiran has been shown to inhibit viral replication, translation, and secretion of HBsAg, and may provide or contribute to a functional cure of chronic HBV infections. An siRNA targeting HBV mRNA can have multiple antiviral effects, including degradation of the pgRNA, thus inhibiting viral replication, and degradation of all viral mRNA transcripts, thereby preventing expression of viral proteins. This may result in the return of a functional immune response directed against HBV, either alone or in combination with other therapies. The ability of elebsiran to reduce HBsAg-containing noninfectious subviral particles also distinguishes it from currently available treatments.

[0083] Elebsiran targets and inhibits expression of an mRNA encoded by an HBV genome according to NCBI Reference Sequence NC_003977.2 (GenBank Accession No. GE21326584) (SEQ ID NO:1). More specifically, elebsiran targets an mRNA encoded by a portion of the HBV genome comprising the sequence GTGTGCACTTCGCTTCAC (SEQ ID NO:2), which corresponds to nucleotides 1579-1597 of SEQ ID NO:1. Because transcription of the HBV genome results in polycistronic, overlapping RNAs, elebsiran significantly inhibits expression of most or all HBV transcripts.47181072933.1

[0084] Exemplary methods for synthesizing elebsiran, and experimental data demonstrating silencing of HBV gene expression, are described in International Application Publication No. W02020 / 036862A1 and U. S. Patent Application Publication No. US20210332365 Al, which methods and data are incorporated herein by reference. For example, HBV sense and antisense strand sequences may be synthesized at 1 pmol scale on aMermade 192 synthesizer (BioAutomation) using solid support mediated phosphoramidite chemistry. The solid support may be a controlled pore glass (500 A) loaded with custom GalNAc ligand or universal solid support (AM biochemical). Ancillary synthesis reagents, 2'-F and 2'-O-Methyl RNA. and deoxy phosphoramidites may be obtained from Thermo-FisherTM (Milwaukee, WI) and Hongene (China). 2'F 2'-O-Methyl, GNA (glycol nucleic acids), 5'-phosphate, and abasic modifications may be introduced employing the corresponding phosphoramidites. Synthesis of 3' GalNAc conjugated single strands may be performed on a GalNAc modified CPG support. A custom CPG universal solid support may be used for the synthesis of antisense single strands. Coupling time for all phosphoramidites (100 mM in acetonitrile) may be 5 minutes employing 5-Ethylthio-IH-tetrazole (ETT) as activator (0.6 M in acetonitrile). Phosphorothioate linkages may be generated using a 50 mM solution of 3-((Dimethylamino-methylidene) amino)-3H-l,2,4-dithiazole-3-thione (DDTT, obtained from Chemgenes (Wilmington, MA, USA)) in anhydrous acetonitrile / pyridine (1: 1 v / v). Oxidation time may be 3 minutes. All sequences may be synthesized with final removal of the DMT group (" DMT off'). Upon completion of the solid phase synthesis, oligoribonucleotides may be cleaved from the solid support and deprotected in sealed 96 deep well plates using 200 pL Aqueous Methylamine reagents at 60°C for 20 minutes. At the end of cleavage and deprotection step, the synthesis plate may be allowed to come to room temperature and precipitated by addition of ImL of acetontile: ethanol mixture (9: 1). The plates may be cooled at -80°C for 2 hours, and the supernatant decanted carefully with the aid of a multi-channel pipette. The oligonucleotide pellet may be re-suspended in 20mM NaOAc buffer and desalted using a 5 mL HiTrapTM size exclusion column (GE HealthcareTM) on an AKTA Purifier System equipped with an A905 autosampler and a48181072933.1Frac 950 fraction collector. Desalted samples may then be collected in 96-well plates. Samples from each sequence may be analyzed by LC-MS to confirm the identity, by UV (260 nm) for quantification, and by IEX chromatography to determine purity. Annealing of HBV single strands may be performed on a Tecan liquid handling robot. Equimolar mixture of sense and antisense single strands may be combined and annealed in 96-well plates. After combining the complementary single strands, the 96-well plate may be sealed tightly and heated in an oven at 100°C for 10 minutes and allowed to come slowly to room temperature over a period of 2-3 hours. The concentration of each duplex may be normalized to lOpM in IX PBS.

[0085] Elebsiran has a sense strand comprising 5'-GUGUGCACUUCGCUUCACA -3* (SEQ ID NO:3) and an antisense strand comprising 5'- UGUGAAGCGAAGUGCACACUU -3' (SEQ ID NO:4), wherein the nucleotides include 2'-fluoro (2'F) and 2'-O-methoxy (2'OMe) ribose sugar modifications, phosphorothioate backbone modifications, and a glycol nucleic acid (GNA) modification, and a triantennary N-acetyl-galactosamine (GalNAc) ligand is conjugated to the 3' end of the sense strand, to facilitate delivery to hepatocytes through the asialoglycoprotein receptor (ASGPR). Including modifications, the sense strand of elebsiran comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO:5) attached to a ligand (L) at the 3' end, and the antisense strand comprises 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO:6), wherein the modifications are abbreviated as shown in Table 1.Table 1. Abbreviations of nucleotide monomers used in modified nucleic acid sequence representation. It will be understood that, unless otherwise indicated, these monomers, when present in an oligonucleotide, are mutually linked by 5'-3'-phosphodiester bonds.Abbreviation Nucleotide(s)A adenosine-3 '-phosphateAf 2'-fluoroadenosine-3'-phosphateAfs 2'-fluoroadenosine-3'-phosphorothioateAs adenosine-3'-phosphorothioateC cytidine-3'-phosphateCf 2'-fluorocytidine-3'-phosphateCfs 2'-fluorocytidine-3'-phosphorothioate49181072933.1Abbreviation Nucleotide(s)Cs cvtidine-3'-phosphorothioateG guanosine-3'-phosphateGf 2'-fluoroguanosine-3'-phosphateGfs 2'-fluoroguanosine-3'-phosphorothioateGs guanosine-3'-phosphorothioateU uridine-3'-phosphateUf 2'-fluorouridine-3'-phosphateUfs 2'-fluorouridine -3'-phosphorothioateUs uridine -3'-phosphorothioatea 2'-O-methvladenosine-3'-phosphateas 2'-O-methyladenosine-3'- phosphorothioatec 2'-O-methylcvtidine-3'-phosphatecs 2'-O-methylcytidine-3'- phosphorothioateg 2'-O-methylguanosine-3'-phosphategs 2'-O-methylguanosine-3'- phosphorothioateu 2' -O-methy luri dine-3 ' -phosphateUS 2'-O-methyluridine-3'-phosphorothioates phosphorothioate linkageL HO- - 2. H Hfit A.- ■ r - A + VAciiO g [. OH 1 / k 0 VA-A H H 'A H T ** AcW I1S -J 9HO '' JiV— AA..... j.H H(Agn) adenosine-glvcol nucleic acid (GNA)

[0086] The triantennary N-acetyl-galactosamme (GalNAc) ligand (indicated by " L" in above) conjugated to the 3' end of the sense strand is:50181072933.1The ligand is conjugated to the 3' end of the sense strand as shown in the following schematic:wherein X is O.b. Pharmaceutical Compositions and Delivery of siRNA

[0087] In some embodiments, pharmaceutical compositions containing an siRNA, as described herein, and a pharmaceutically acceptable carrier or excipient are provided. The pharmaceutical composition containing the siRNA can be used to treat HBV infection. Such pharmaceutical compositions are typically formulated based on51181072933.1the mode of delivery. For example, compositions may be formulated for systemic administration via parenteral delivery, e.g., by subcutaneous (SC) delivery.

[0088] A "pharmaceutically acceptable carrier" or "excipient" is a pharmaceutically acceptable solvent, suspending agent, or any other pharmacologically inert vehicle for delivering one or more agents, such as nucleic acids, to an animal. The excipient can be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with the agent (e.g., a nucleic acid) and the other components of a given pharmaceutical composition. Typical pharmaceutically acceptable carriers or excipients include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate); disintegrants (e.g., starch, sodium starch glycolate); and wetting agents (e.g, sodium lauryl sulphate).

[0089] Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration that do not deleteriously react with nucleic acids can also be used to formulate siRNA compositions. Suitable pharmaceutically acceptable carriers for formulations used in non-parenteral delivery include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone, and the like.

[0090] Formulations for topical administration of nucleic acids can include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions can also contain buffers, diluents, and other suitable additives.Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration that do not deleteriously react with nucleic acids can be used.52181072933.1

[0091] In some embodiments, administration of pharmaceutical compositions and formulations described herein can be topical (e.g., by a transdermal patch), pulmonary (e.g, by inhalation or insufflation of powders or aerosols, including by nebulizer); intratracheal; intranasal; epidermal and transdermal; oral; or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, and intramuscular injection or infusion; subdermal administration (e.g, via an implanted device); or intracranial administration (e.g, by intraparenchymal, intrathecal, or intraventricular, administration).

[0092] In some embodiments, the pharmaceutical composition comprises a sterile solution of elebsiran formulated in water for subcutaneous injection. In some embodiments, the pharmaceutical composition comprises a sterile solution of elebsiran formulated in water for subcutaneous injection at a free acid concentration of 200 mg / mL.

[0093] In some embodiments, the pharmaceutical compositions containing elebsiran are administered in dosages sufficient to inhibit expression of an HBV gene. In some embodiments, a dose of an siRNA is in the range of 0.001 to 200.0 milligrams per kilogram body weight of the recipient per day, or in the range of 1 to 50 milligrams per kilogram body weight per day. For example, an siRNA can be administered at 0.01 mg / kg, 0.05 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 3 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg per single dose. The pharmaceutical composition can be administered once daily, or it can be administered as two, three, or more sub-doses at appropriate intervals throughout the day or even using continuous infusion or delivery through a controlled release formulation. In that case, the siRNA contained in each sub-dose must be correspondingly smaller in order to achieve the total daily dosage. The dosage unit can also be compounded for delivery over several days, e.g, using a conventional sustained release formulation which provides sustained release of the siRNA over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the technology described herein. In such embodiments, the dosage unit contains a corresponding multiple of the daily dose.53181072933.1

[0094] In some embodiments, a pharmaceutical composition comprising elebsiran contains elebsiran at a dose of 0.8 mg / kg, 1.7 mg / kg, 3.3 mg / kg, 6.7 mg / kg, or 15 mg / kg.

[0095] In some embodiments, a pharmaceutical composition comprising elebsiran contains elebsiran at a dose of 20 mg, 50 mg, 100 mg, 150 mg, 200 mg. 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg. 550 mg, 600 mg. 650 mg, 700 mg. 750 mg, 800 mg, 850 mg, or 900 mg. In some embodiments, the pharmaceutical composition comprises elebsiran at a dose of from 20 mg to 900 mg. In some embodiments, the pharmaceutical composition comprises elebsiran at a dose of from 100 mg to 300 mg. In some embodiments, the pharmaceutical composition comprises elebsiran at a dose of 200 mg.III. Anti-HBV Antibodies

[0096] The present disclosure also provides, in some embodiments, methods of treatment involving administering tobevibart, an anti-HBV antibody.a. Tobevibart

[0097] Tobevibart is an antibody that binds to the antigenic loop region of HBsAg.

[0098] The envelope of the hepatitis B virus contains three " HBV envelope proteins" (also known as " HBsAg", "hepatitis B surface antigen"): S protein (for "small", also referred to as S-HBsAg), M protein (for "middle" or medium, also referred to as M-HBsAg). and L protein (for "large", also referred to as L-HBsAg). S-HBsAg, M-HBsAg, and L- HBsAg share the same C-terminal extremity (also referred to as " S domain", 226 amino acids), which corresponds to the S protein (S-HBsAg) and which is involved in virus assembly and infectivity. S-HBsAg, M-HBsAg. and L-HBsAg are synthesized in the endoplasmic reticulum (ER), assembled, and secreted as particles through the Golgi apparatus. The S domain comprises four predicted transmembrane (TM) domains, whereby both the N-terminus and the C-terminus of the S domain are exposed to the lumen. The transmembrane domains TM1 and TM2 are both necessary for cotranslational protein integration into the ER membrane and the transmembrane domains TM3 and TM4 are located in the C-terminal third of the S domain. The 54181072933.1"antigenic loop region" of HBsAg is located between the predicted TM3 and TM4 transmembrane domains of the S domain of HBsAg, whereby the antigenic loop region comprises amino acids 101 - 172 of the S domain (Salisse J and Sureau C, Journal of Virology 2009, 83:9321-8). An important determinant of infectivity resides in the antigenic loop region of HBV envelope proteins. In particular, residues between 119 and 125 of the HBsAg contain a CXXC motif, which has been demonstrated to be the most important sequence required for the infectivity of HBV (Jaoude GA and Sureau C, Journal of Virology 2005, 79:10460-6).

[0099] As used herein, the S domain of HBsAg refers to an amino acid sequence as set forth in SEQ ID NO:7 (shown below) or to natural or artificial sequence variants thereof.MENITSGFLGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTT VCLGQNSQSPTSNHSPTSCPPTCPGYRWMCLRRFIIFLFILLLCLIF LLVLLDYQGMLPVCPLIPGSSTTSTGPCRTCMTTAQGTSMYPSCC CTKPSDGNCTCIPIPSSWAFGKFLWEWASARFSWLSLLVPFVQWF VGLSPTVWLSVIWMMWYWGPSLYSILSPFLPLLPIFFCLWVYI(SEQ ID NO:7; amino acids 101 - 172 are shown underlined)

[0100] For example, the expression "amino acids 101 - 172 of the S domain" refers to the amino acid residues from positions 101 - 172 of the polypeptide according to SEQ ID NO:7. However, a person skilled in the art will understand that mutations or variations (including, but not limited to, substitution, deletion and / or addition, for example, HBsAg of a different genotype or a different HBsAg mutant as described herein) may occur naturally in the amino acid sequence of the S domain of HBsAg or be introduced artificially into the amino acid sequence of the S domain of HBsAg without affecting its biological properties. Therefore, the term " S domain of HBsAg" comprises all such polypeptides, for example, including the polypeptide according to SEQ ID NO: 7 and its natural or artificial mutants. In addition, when sequence fragments of the S domain of HBsAg are described herein (e.g. amino acids 101 - 172 or amino acids 120 -130 of the S domain of HBsAg), they include not only the corresponding sequence fragments of SEQ ID NO:7, but also the corresponding55181072933.1sequence fragments of its natural or artificial mutants. For example, the expression "amino acid residues from positions 101 - 172 of the S domain of HBsAg" includes amino acid residues from positions 101 - 172 of SEQ ID NO: 7 and the corresponding fragments of its mutants (natural or artificial mutants).

[0101] As used herein, the expression "corresponding sequence fragments" or "corresponding fragments" refers to fragments that are located in equal positions of sequences when the sequences are subjected to optimized alignment, namely, the sequences are aligned to obtain a highest percentage of identity. The M protein (M-HBsAg) corresponds to the S protein extended by an N-terminal domain of 55 amino acids called "preS2". The L protein (L-HBsAg) corresponds to the M protein extended by an N-terminal domain of 108 amino acids called "preSl" (genoty pe D). The preSl and preS2 domains of the L protein can be present either at the inner face of viral particles (on the cytoplasmic side of the ER), playing a crucial role in virus assembly, or on the outer face (on the luminal side of the ER), available for the interaction with target cells and necessary’ for viral infectivity. Moreover, HBV surface proteins (HBsAgs) are not only incorporated into virion envelopes but also spontaneously bud from ER-Golgi intermediate compartment membranes to form empty "subviral particles" (SVPs) that are released from the cell by secretion.

[0102] Since all three HBV envelope proteins S-HBsAg, M-HBsAg, and L-HBsAg comprise the S domain, all three HBV envelope proteins S-HBsAg, M-HBsAg, and L-HBsAg also comprise the "antigenic loop region". Accordingly, an antibody or an antigen binding fragment thereof that binds to the antigenic loop region of HBsAg binds to all three HBV envelope proteins: S-HBsAg, M-HBsAg, and L-HBsAg.

[0103] The anti -HBV antibody of the combination therapy neutralizes infection with hepatitis B vims. To study and quantitate virus infectivity (or "neutralization") in the laboratory the person skilled in the art knows various standard "neutralization assays." For a neutralization assay, animal viruses are typically propagated in cells and / or cell lines. In the context of the present disclosure, for a neutralization assay, cultured cells may be incubated with a fixed amount of HBV in the presence (or absence) of the antibody to be tested. As a readout, the levels of hepatitis B surface56181072933.1antigen (HBsAg) or hepatitis B e antigen (HBeAg) secreted into the cell culture supernatant may be used and / or HBeAg staining may be assessed. In one embodiment of a HBV neutralization assay, cultured cells, for example HepaRG cells, in particular differentiated HepaRG cells, are incubated with a fixed amount of HBV in the presence or absence of the antibody to be tested, for example for 16 hours at 37°C. The incubation may be performed in a medium (e.g.. supplemented with 4% PEG 8000). After incubation, cells may be washed and further cultivated. To measure virus infectivity', the levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) secreted into the culture supernatant, e.g., from day 7 to day 11 post-infection, may be determined by enzyme-linked immunosorbent assay (ELISA). Additionally, HBeAg staining may be assessed in an immunofluorescence assay.

[0104] Table 2 shows the amino acid sequences of the CDRs, heavy’ chain variable region (VH), light chain variable region (VL), full-length heavy chain (HC), and full-length light chain (LC) of tobevibart.Table 2, Amino acid sequences for tobevibart.Antibody Region Amino Acid Sequence SEQ ID NO CDRH1 GRIFRSFY8 (short) CDRH2 NQDGSEK9(long) CDRH2 INQDGSEK10 CDRH3 AAWSGNSGGMDV11 CDRL1 KLGNKN12 (short) CDRL2 EVK13 (long) CDRL2 VIYEVKYRP14 CDRL3 QTFDSTTVV1557181072933.1VHELQLVESGGGWVQPGGSQRLSCAASGRI 16 FRSFYMSWVRQAPGKGLEWVATINQDG SEKLYVDSVKGRFTISRDNAKNSLFLQM NNLRVEDTAVYYCAAWSGNSGGMDVW GQGTTVSVSS VL SYELTQPPSVSVSPGQTVSIPCSGDKLGN17 KNVAWFQHKPGQSPVLVIYEVKYRPSGI PERFSGSNSGNTATLTISGTQAMDEAAYF CQTFDSTTVVFGGGTRLTVL HC ELQLVESGGGWVQPGGSQRLSCAASGRI18 FRSFYMSWVRQAPGKGLEWVATINQDG SEKLYVDSVKGRFTISRDNAKNSLFLQM NNLRVEDTAVYYCAAWSGNSGGMDVW GQGTTVSVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLAGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPLPEEK TISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVLHEALHSHYTQKSLSLSPGK LC SYELTQPPSVSVSPGQTVSIPCSGDKLGN19 KNVAWFQHKPGQSPVLVIYEVKYRPSGI PERFSGSNSGNTATLTISGTQAMDEAAYF CQTFDSTTVVFGGGTRLTVLGQPKAAPS VTLFPPSSEELQANKATLVCLISDFYPGA VTVAWKADS SPVKAGVETTTPSKQSNNK YAAS S YLSLTPEQWKSHRSYS CQVTHEG STVEKTVAPTECS58181072933.1

[0105] Exemplary methods for synthesizing antibodies having sequences shown in Table 2, and experimental data demonstrating binding and neutralization by tobevibart, are described in International Application Publication No.W02020 / 132091 A2 and U. S. Patent Application Publication No. US20220127336A1, which methods and data are incorporated herein by reference. For example, antibodies, antigen binding fragments, and fusion proteins according to the disclosure can be made by any method known in the art. The general methodology for making monoclonal antibodies using hybridoma technology is well known. In a specific example, B cells producing the antibody may be transformed with EBV and a polyclonal B cell activator. Additional stimulants of cellular growth and differentiation (such as IL 2 and IL- 15) may optionally be added during the transformation step to further enhance the efficiency. The immortalized B cells produced using these methods can then be cultured using methods known in the art and antibodies isolated therefrom. In another specific example, plasma cells may be cultured in limited numbers, or as single plasma cells in microwell culture plates, and antibodies and RNA can be isolated from the plasma cell cultures. The RNA can be analyzed by PCR using methods known in the art. The VH and VL regions of the antibodies can be amplified by RT-PCR (reverse transcriptase PCR), sequenced, and cloned into an expression vector that is then transfected into HEK293T cells or other host cells. The cloning of nucleic acid in expression vectors, the transfection of host cells, the culture of the transfected host cells and the isolation of the produced antibody can be done using any methods know n to one of skill in the art. Antibodies may be further purified, if desired, using filtration, centrifugation, and various chromatographic methods, such as HPLC or affinity chromatography.Techniques for purification of antibodies, e.g., monoclonal antibodies, including techniques for producing pharmaceutical-grade antibodies, are well known in the art. Furthermore, standard techniques of molecular biology may be used to prepare DNA sequences encoding the antibodies or antibody fragments of the present description. Desired DNA sequences may be synthesized completely or in part using oligonucleotide synthesis techniques. Site-directed mutagenesis and polymerase chain reaction (PCR) techniques may be used as appropriate. Any suitable host cell / vector59181072933.1system may be used for expression of the DNA sequences encoding the antibody or fusion protein molecules of the present disclosure or fragments thereof. Bacterial, e.g, E. coli, and other microbial systems may be used, in part, for expression of antibody fragments. Eukaryotic, e.g., mammalian, host cell expression systems may be used for production of larger antibody molecules, including complete antibody molecules.

[0106] An antibody of the present disclosure may comprise: (i) CDRH1, CDRH2, and CDRH3 amino acid sequences according to SEQ ID NOs:8, 9 or 10, and 11, respectively; and (ii) CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NOs:12, 13 or 14, and 15, respectively.

[0107] An antibody of the present disclosure may comprise: (i) the VH amino acid sequence according to SEQ ID NOs: 16; and (ii) the VL amino acid sequence according to SEQ ID NO: 17.

[0108] In some embodiments, a binding protein (e.g., antibody or an antigen binding fragment thereof) comprises an Fc moiety. As used herein, the term "Fc moiety" refers to a sequence comprising or derived from a portion of an immunoglobulin heavy chain beginning in the hinge region just upstream of the papain cleavage site (e.g., residue 216 in native IgG, taking the first residue of heavy chain constant region to be 114) and ending at the C-terminus of the immunoglobulin heavy chain.

[0109] Tobevibart comprises a Fc moiety containing amino acid modifications that improve binding affinity for FcRn and, in some embodiments, thereby extend in vivo half-life of a molecule comprising the Fc moiety (e.g., as compared to a reference Fc moiety or antibody that does not comprise the modification(s)). For example, tobevibart comprises the half-life-extending M428L / N434S mutations that increase binding affinity of an Fc moiety to an FcRn receptor.

[0110] Tobevibart comprises a Fc moiety containing amino acid modifications that improve binding affinity to certain Fey receptors. For example, tobevibart comprises G236A / A330L / I332E mutations that increase binding affinity of an Fc moiety to Fey receptors FcyllA and FcylllA.b. Pharmaceutical Compositions and Delivery of Antibody60181072933.1

[0111] In some embodiments, an antibody of the combination therapy is provided as a pharmaceutical composition, which includes the anti-HBV antibody and optionally, a pharmaceutically acceptable carrier. In some embodiments, a composition may include an anti-HBV antibody, wherein the antibody may make up at least 50% by weight (e.g., 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) of the total protein in the composition. In such a composition, the antibody may be in purified form.

[0112] Pharmaceutical compositions of the anti-HBV antibody may include an antimicrobial, particularly if packaged in a multiple dose format. They may comprise detergent, e.g., a Tween (polysorbate), such as Tween 80. When present, detergents are typically present at low levels, e.g., less than 0.01%. Compositions may also include sodium salts (e.g., sodium chloride) for tonicity. For example, in some embodiments, a pharmaceutical composition comprises NaCl at a concentration of 10±2mg / ml.

[0113] Further, pharmaceutical compositions may comprise a sugar alcohol (e.g, mannitol) or a disaccharide (e.g, sucrose or trehalose), e.g., at around 15-30 mg / ml (e.g., 25 mg / ml), particularly if they are to be lyophilized or if they include material which has been reconstituted from lyophilized material. The pH of a composition for lyophilization may be adjusted to between 5 and 8, or between 5.5 and 7, or around 6.1 prior to lyophilization.

[0114] An antibody composition of the present disclosure may also comprise one or more immunoregulatory agents. In some embodiments, one or more of the immunoregulatory agents include(s) an adjuvant.

[0115] Methods of preparing a pharmaceutical composition of the anti-HBV antibody may include the steps: (i) preparing the antibody; and (ii) admixing the purified antibody with one or more pharmaceutically acceptable carriers.

[0116] In some embodiments, a pharmaceutical composition comprising tobevibart described herein contains tobevibart at a dose of 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. In some embodiments, a pharmaceutical composition comprising tobevibart contains tobevibart at a dose of from 100 mg to 300 mg. In some embodiments, a pharmaceutical composition comprising tobevibart contains tobevibart61181072933.1at a dose of from 200 mg to 400 mg. In some embodiments, a pharmaceutical composition comprising tobevibart contains tobevibart at a dose of 300 mg.IV. Methods of Treatment using Combination Therapies

[0117] In some embodiments, the present disclosure provides methods for treating HDV infection or a HDV-associated disease in a subject.

[0118] In some embodiments, methods for treating HDV infection or a HDV-associated disease in a subject are provided, wherein the method comprises administering elebsiran and tobevibart to the subject.

[0119] In some embodiments, methods for treating HDV infection or a HDV-associated disease in a subject are provided, wherein the method comprises administering elebsiran and tobevibart to the subject, and also administering a nucleoside / nucleotide reverse transcriptase inhibitor to the subject. As used herein, "nucleoside / nucleotide reverse transcriptase inhibitor" or "nucleos(t)ide reverse transcriptase inhibitor" (NRTI) refers to an inhibitor of DNA replication that is structurally similar to a nucleotide or nucleoside and specifically inhibits replication of the HBV cccDNA by inhibiting the action of HBV polymerase, and does not significantly inhibit the replication of the host (e.g., human) DNA. Such inhibitors include tenofovir, tenofovir disoproxil fumarate (TDF), tenofovir disoproxil (TD), tenofovir alafenamide (TAF), lamivudine, adefovir, adefovir dipivoxil, entecavir (ETV), telbivudine, AGX-1009, emtricitabine (FTC), clevudine, ritonavir, dipivoxil, lobucavir, famvir, N-Acetyl-Cysteine (NAC), PC 1323, theradigm-HBV, thymosinalpha, ganciclovir, besifovir (ANA-380 / LB-80380), and tenofvir-exaliades (TLX / CMX157). In some embodiments, the NRTI is tenofovir. In some embodiments, the NRTI is tenofovir disoproxil fumarate (TDF). In some embodiments, the NRTI is disoproxil (TD). In some embodiments, the NRTI is entecavir (ETV). In some embodiments, the NRTI is lamivudine. In some embodiments, the NRTI is adefovir or adefovir dipivoxil.

[0120] As used herein, a "subject" is human that has a hepatitis B virus (HBV) infection.62181072933.1

[0121] As used herein, the terms "treating" or "treatment" refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more signs or symptoms associated with unwanted HBV gene expression or HBV replication, e.g., the presence of serum or liver HBV cccDNA, the presence of serum HBV DNA, the presence of serum or liver HBV antigen, e.g., HBsAg or HBeAg, elevated ALT, elevated aspartate transaminase (AST) (normal range is typically considered about 10 to 34 U / L), the absence of or low level of anti-HBV antibodies; a liver injury; cirrhosis; delta hepatitis; acute hepatitis B; acute fulminant hepatitis B; chronic hepatitis B; liver fibrosis; end-stage liver disease; hepatocellular carcinoma; serum sickness-like syndrome; anorexia; nausea; vomiting, low-grade fever; myalgia; fatigability; disordered gustatory acuity and smell sensations (aversion to food and cigarettes); or right upper quadrant and epigastric pain (intermittent, mild to moderate); hepatic encephalopathy; somnolence; disturbances in sleep pattern; mental confusion; coma; ascites; gastrointestinal bleeding; coagulopathy; jaundice; hepatomegaly (mildly enlarged, soft liver); splenomegaly; palmar erythema; spider nevi; muscle wasting; spider angiomas; vasculitis; variceal bleeding; peripheral edema; gynecomastia; testicular atrophy; abdominal collateral veins (caput medusa); ALT levels higher than AST levels; elevated gamma-glutamyl transpeptidase (GGT) (normal range is typically considered about 8 to 65 U / L) and alkaline phosphatase (ALP) levels (normal range is typically considered about 44 to 147 IU / L (international units per liter), not more than 3 times the ULN); slightly low albumin levels; elevated serum iron levels; leukopenia (i.e., granulocytopenia); lymphocytosis; increased erythrocyte sedimentation rate (ESR); shortened red blood cell survival; hemolysis; thrombocytopenia; a prolongation of the international normalized ratio (INR); presence of serum or liver HBsAg, HBeAg, Hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM); hepatitis B surface antibody (anti-HBs), hepatitis B e antibody (anti-HBe), or HBV DNA; increased bilirubin levels; hyperglobulinemia; the presence of tissue-nonspecific antibodies, such as anti-smooth muscle antibodies (ASMAs) or antinuclear antibodies (ANAs) (10-20%); the presence of tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%); elevated levels of rheumatoid factor (RF); low platelet and white blood63181072933.1cell counts; lobular, with degenerative and regenerative hepatocellular changes, and accompanying inflammation; and predominantly centrilobular necrosis, whether detectable or undetectable. The likelihood of developing, e.g. liver fibrosis, is reduced, for example, when an individual having one or more risk factors for liver fibrosis, e.g., chronic hepatitis B infection, either fails to develop liver fibrosis or develops liver fibrosis with less severity relative to a population having the same risk factors and not receiving treatment as described herein. " Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment.

[0122] As used herein, the terms "preventing" or "prevention" refer to the failure to develop a disease, disorder, or condition, or the reduction in the development of a sign or symptom associated with such a disease, disorder, or condition (e.g., by a clinically relevant amount), or the exhibition of delayed signs or symptoms delayed (e.g., by days, weeks, months, or years). Prevention may require the administration of more than one dose.

[0123] Doses are often expressed in relation to body weight. Thus, a dose which is expressed as [g, mg, or other unit] / kg (or g, mg, etc.) usually refers to [g, mg, or other unit] "per kg (or g, mg, etc.) body weight," even if the term "body weight" is not explicitly mentioned.

[0124] " Therapeutically effective amount," as used herein, is intended to include the amount of an siRNA, an anti-HBV antibody, or other active agent (e.g., tenofovir), that, when administered to a patient for treating a subject having an HBV infection or HBV-associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing or maintaining the existing disease or one or more symptoms of disease). The "therapeutically effective amount" may vary' depending on the active agent(s), how they are administered, the disease and its severity, and the history, age, weight, family history, genetic makeup, stage of pathological processes mediated by HBV gene expression, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. A therapeutically effective amount may require the administration of more than one dose.64181072933.1

[0125] A "therapeutically effective amount" also includes an amount of an siRNA, an anti-HBV antibody, or other active agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any treatment. Therapeutic agents (e.g., siRNAs, anti-HBV antibodies) used in the methods of the present disclosure may be administered in a sufficient amount to produce a reasonable benefit / risk ratio applicable to such treatment.

[0126] The term "sample," as used herein, includes a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum, and serosal fluids, plasma, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from the liver (e.g., whole liver or certain segments of liver or certain types of cells in the liver, such as, e.g., hepatocytes). In certain embodiments, a "sample derived from a subject" refers to blood, or plasma or serum obtained from blood drawn from the subject. In further embodiments, a "sample derived from a subject" refers to liver tissue (or subcomponents thereof) or blood tissue (or subcomponents thereof, e.g., serum) derived from the subject.

[0127] In some embodiments, treatment of HBV infection results in a "functional cure" of hepatitis B. As used herein, functional cure is understood as clearance of circulating HBsAg and may be accompanied by conversion to a status in which HBsAg antibodies become detectable using a clinically relevant assay. For example, detectable antibodies can include a signal higher than 10 mIU / ml as measured by Chemiluminescent Microparticle Immunoassay (CMIA) or any other immunoassay. Functional cure does not require clearance of all replicative forms of HBV (e.g, cccDNA from the liver). Anti-HBs seroconversion occurs spontaneously in about 0.2-1% of chronically infected patients per year. However, even after anti-HBs seroconversion, low level persistence of HBV is often observed for decades indicating that a functional rather than a complete cure occurs. Without being bound to a particular mechanism, the immune system may be able to keep HBV in check under conditions in65181072933.1which a functional cure has been achieved. A functional cure permits discontinuation of any treatment for the HBV infection. However, it is understood that a "functional cure" for HBV infection may not be sufficient to prevent or treat diseases or conditions that result from HBV infection, e.g., liver fibrosis, HCC, or cirrhosis. In some specific embodiments, a "functional cure" can refer to a sustained reduction in serum HBsAg, such as <1 lU / mL, for at least 3 months, at least 6 months, or at least one year following the initiation of a treatment regimen or the completion of a treatment regimen.

[0128] As used herein, the term " Hepatitis B virus-associated disease" or " HBV-associated disease," is a disease or disorder that is caused by, or associated with HBV infection or replication. The term " HBV-associated disease" includes a disease, disorder or condition that would benefit from reduction in HBV gene expression or replication. Non-limiting examples of HBV-associated diseases include, for example, hepatitis D virus infection, delta hepatitis, acute hepatitis B; acute fulminant hepatitis B; chronic hepatitis B; liver fibrosis; end-stage liver disease; and hepatocellular carcinoma.

[0129] In some embodiments, an HBV-associated disease is chronic hepatitis B. Chronic hepatitis B is defined by one of the following criteria: (1) positive serum HBsAg, HBV DNA, or HBeAg on two occasions at least 6 months apart (any combination of these tests performed 6 months apart is acceptable); or (2) negative immunoglobulin M (IgM) antibodies to HBV core antigen (IgM anti-HBc) and a positive result on one of the following tests: HBsAg, HBeAg, or HBV DNA. Chronic HBV typically includes inflammation of the liver that lasts more than six months.Subjects having chronic HBV are HBsAg positive and have either high viremia (> 104HBV-DNA copies / ml blood) or low viremia (<103HBV-DNA copies / ml blood). In certain embodiments, subjects have been infected with HBV for at least five years. In certain embodiments, subjects have been infected with HBV for at least ten years. In certain embodiments, subjects became infected with HBV at birth. Subjects having chronic hepatitis B disease can be immune tolerant or have an inactive chronic infection without any evidence of active disease, and they are also asymptomatic. Patients with chronic active hepatitis, especially during the replicative state, may have symptoms similar to those of acute hepatitis. Subjects having chronic hepatitis B disease may have66181072933.1an active chronic infection accompanied by necroinflammatory liver disease, have increased hepatocyte turn-over in the absence of detectable necroinflammation, or have an inactive chronic infection without any evidence of active disease, and they are also asymptomatic. The persistence of HBV infection in chronic HBV subjects is the result of cccHBV DNA. In some embodiments, a subject having chronic HBV is HBeAg positive. In some other embodiments, a subject having chronic HBV is HBeAg negative. Subjects having chronic HBV have a level of serum HBV DNA of less than 105 and a persistent elevation in transaminases, for examples ALT, AST, and gammaglutamyl transferase. A subject having chronic HBV may have a liver biopsy score of less than 4 (e.g, a necroinflammatory score). In some embodiments, ALT ULN values are 34 lU / mL for females and 43 lU / mL for males.

[0130] In some embodiments, an HBV-associated disease is hepatitis D virus infection. Hepatitis D virus or hepatitis delta virus (HDV) is a human pathogen.However, the virus is defective and depends on obligatory' helper functions provided by HBV for transmission; indeed. HDV requires an associated or pre-existing HBV infection to become infectious and thrive, in particular, the viral envelope containing the surface antigen of hepatitis B. HDV can lead to severe acute and chronic forms of liver disease in association with HBV. Hepatitis D infection or delta hepatitis is highly endemic to several African countries, the Amazonian region, and the Middle East, while its prevalence is low in industrialized countries, except in the Mediterranean.

[0131] Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection). Both superinfection and coinfection with HDV typically result in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased chance of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%.

[0132] In some embodiments, an HBV-associated disease is acute hepatitis B. Acute hepatitis B includes inflammation of the liver that lasts less than six months.67181072933.1Typical symptoms of acute hepatitis B are fatigue, anorexia, nausea, and vomiting. Very high aminotransferase values (>1000 U / L) and hyperbilirubinemia are often observed. Severe cases of acute hepatitis B may progress rapidly to acute liver failure, marked by poor hepatic synthetic function. This is often defined as a prothrombin time (PT) of 16 seconds or an international normalized ratio (INR) of 1.5 in the absence of previous liver disease. Acute hepatitis B may evolve into chronic hepatitis B.

[0133] In some embodiments, an HBV-associated disease is acute fulminant hepatitis B. A subject having acute fulminant hepatitis B has symptoms of acute hepatitis and the additional symptoms of confusion or coma (due to the liver's failure to detoxify chemicals) and bruising or bleeding (due to a lack of blood clotting factors).

[0134] Subjects having an HBV infection, e.g., chronic HBV, may develop liver fibrosis. Accordingly, in some embodiments, an HBV-associated disease is liver fibrosis. Liver fibrosis, or cirrhosis, is defined histologically as a diffuse hepatic process characterized by fibrosis (excess fibrous connective tissue) and the conversion of normal liver architecture into structurally abnormal nodules.

[0135] Subjects having an HBV infection, e.g.. chronic HBV, may develop endstage liver disease. Accordingly, in some embodiments, an HBV-associated disease is end-stage liver disease. For example, liver fibrosis may progress to a point where the body may no longer be able to compensate for, e.g., reduced liver function, as a result of liver fibrosis (i.e., decompensated liver), and result in, e.g., mental and neurological symptoms and liver failure.

[0136] Subjects having an HBV infection, e.g., chronic HBV, may develop hepatocellular carcinoma (HCC), also referred to as malignant hepatoma. Accordingly, in some embodiments, an HBV-associated disease is HCC. HCC commonly develops in subjects having CHB and may be fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cell), or clear cell.

[0137] An " HDV-associated disease" or a Hepatitis D-virus-associated disease" is a disease or disorder associated with expression of an HDV. Exemplary HDV-associated diseases include hepatitis B virus infection, acute hepatits B, acute hepatitis68181072933.1D; acute fulminant hepatitis D; chronic hepatitis D; liver fibrosis; end-stage liver disease; and hepatocellular carcinoma.

[0138] In some embodiments, the subject has a hepatitis delta virus (HDV) infection with non-cirrhotic or compensated cirrhotic liver disease. " Compensated cirrhosis" patients are partially or fully asymptomatic and usually have Child-Pugh-Turcotte (CPT) scores of 6 or less / Class A. " Decompensated cirrhosis" patients have cirrhosis-related symptomatic complications and usually have CTP scores of 7-15 / Class B or Class C.

[0139] In some embodiments, the subject is an adult.

[0140] In some embodiments of the methods described herein, the anti-HBV antibody is administered subcutaneously. In some embodiments, the anti-HBV antibody is administered every 4 weeks. In some embodiments, the anti-HBV antibody is administered every 8 weeks. In some embodiments, the anti-HBV antibody is administered at a dose of from 100 mg to 300 mg. In some embodiments, the anti-HBV antibody is administered at a dose of 100 mg. In some embodiments, the anti-HBV antibody is administered at a dose of 150 mg. In some embodiments, the anti-HBV antibody is administered at a dose of 200 mg. In some embodiments, the anti-HBV antibody is administered at a dose of 250 mg. In some embodiments, the anti-HBV antibody is administered at a dose of 300 mg. In some embodiments, the subject is administered the anti-HBV antibody for a period of 8 weeks, 24 weeks, 48 weeks, 88 weeks, or 240 weeks. In some embodiments, the anti-HBV antibody is administered subcutaneously every 4 weeks for up to 48 weeks (inclusive) at a dose of 300 mg. In some embodiments, the anti-HBV antibody is administered subcutaneously every 4 weeks for up to 240 weeks (inclusive) at a dose of 300 mg.

[0141] In some embodiments of the methods described herein, the siRNA is administered subcutaneously. In some embodiments, the siRNA is administered every 4 weeks. In some embodiments, the siRNA is administered every 8 weeks. In some embodiments, the siRNA is administered at a dose of from 20 mg to 900 mg. In some embodiments, the siRNA is administered at a dose of from 100 mg to 300 mg. In some embodiments, the siRNA is administered at a dose of 20 mg, 50 mg, 100 mg, 150 mg,69181072933.1200 mg, 250 mg, 300 mg, 400 mg, or 450 mg. In some embodiments, the siRNA is administered at a dose of 200 mg. In some embodiments, the subject is administered the siRNA for a period of 8 weeks, 24 weeks, 48 weeks, 88 weeks, or 240 weeks. In some embodiments, the siRNA is administered subcutaneously every 4 weeks for up to 48 weeks (inclusive) at a dose of 200 mg. In some embodiments, the siRNA is administered subcutaneously every 4 weeks for up to 240 weeks (inclusive) at a dose of 200 mg.

[0142] In some embodiments of the methods described herein, the NRTI is administered orally. In some embodiments, the NRTI is administered daily. In some embodiments, the NRTI is administered at a dose of 300 mg.

[0143] In some embodiments of the methods described herein, the subject achieves one or more of: a HDV RNA < LLOQ. TND; and a ALT < upper limit of normal (ULN). In some embodiments, ALT ULN values are 34 IU / mL for females and 43 lU / mL for males.

[0144] The present disclosure also provides antibodies, siRNAs, and / or NRTIs described herein, and pharmaceutical compositions comprising the same, for use in the aforementioned methods. Uses of the antibodies, siRNAs, and / or NRTIs in the manufacture of medicaments for use in the aforementioned methods are also provided.

[0145] In some embodiments, the present disclosure provides a method of treating hepatitis D virus (HDV) infection in a subject having a normal ALT level (less than the upper limit of normal) before treatment, the method comprising administering to the subject: (a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO:5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO:6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively: Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate,70181072933.12'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively; (Agn) is adenosine-glycol nucleic acid (GNA); s is a phosphorothioate linkage; and L is

[0146] In some embodiments, the light chain CDRL1, CDRL2, and CDRL3 comprise or consist of the amino acid sequences according to SEQ ID NOs: 12, 13 or 14, and 15, respectively. In some embodiments, the heavy chain CDRH1, CDRH2. and CDRH3 comprise or consist of the amino acid sequences according to SEQ ID NOs: 8, 9 or 10, and 11, respectively. In some embodiments, the light chain variable domain (VL) comprises or consists of the amino acid sequence according to SEQ ID NO: 17. In some embodiments, the heavy chain variable domain (VH) comprises or consists of the amino acid sequence according to SEQ ID NO: 16. In some embodiments, the L is conj ugated to the siRNA as shown in the following structure:71181072933.1wherein X is O.

[0147] In some embodiments, the present disclosure provides a method of preventing ALT flares, eliminating ALT flares, or reducing the number of or frequency of ALT flares in a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject: (a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO:6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively; (Agn) is adenosine-glycol nucleic acid (GNA); s is a phosphorothioate linkage; and L isIn some embodiments, the light chain CDRL1, CDRL2, and CDRL3 comprise or consist of the amino acid sequences according to SEQ ID NOs:12, 13 or 14, and 15, respectively. In some embodiments, the heavy chain CDRH1, CDRH2, and CDRH3 comprise or consist of the amino acid sequences according to SEQ ID NOs:8, 9 or 10, and 11, respectively. In some embodiments, the light chain variable domain (VL) comprises or consists of the amino acid sequence according to SEQ ID NO: 17. In some embodiments, the heavy chain variable domain (VH) comprises or consists of the amino 72181072933.1acid sequence according to SEQ ID NO: 16. In some embodiments, the L is conjugated to the siRNA as shown in the following structure:wherein X is O. As used herein, an “ALT flare” refers to ALT levels greater than or equal to five times ULN (> 5 x ULN).

[0148] In some embodiments, the present disclosure provides a finite therapy for treating a hepatitis D virus (HDV) infection. Subjects may exhibit a sustained virologic response (SVR) after treatment for a period of time, and no longer require ongoing therapy. SVR may be indicated by undetectable HDV RNA levels (e.g., HDV RNA target not detected, TND). For example, in some embodiments, the present disclosure provides a method of treating a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject: (a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO:5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate. 2'-73181072933.1fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively; (Agn) is adenosine-glycol nucleic acid (GNA); s is a phosphorothioate linkage; and L iswherein the antibody and siRNA are administered for up to 48 weeks to up to 96 weeks. In some embodiments, the antibody and siRNA are administered for up to 48 weeks. In some embodiments, the antibody and siRNA are administered for up to 72 weeks. In some embodiments, the antibody and siRNA are administered for up to 96 weeks. In some of the aforementioned embodiments, the antibody and siRNA are administered every' 4 weeks.

[0149] In some embodiments, the present disclosure provides a method of treating a subject having a hepatitis D virus (HDV) infection, the method comprising:(1) administering to the subject: (a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy' chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO:5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO:6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively; (Agn) is adenosine-glycol nucleic acid (GNA); s is a phosphorothioate linkage; and L is74181072933.1HO...0Hand(2) if the subject has detectable HDV RNA, continuing the administration of step 1, and if the subject does not have detectable HDV RNA, discontinuing the administration of step 1. In some embodiments, the method further comprises determining a HDV RNA level between step 1 and step 2. In some embodiments, the administering in step 1 is up to 48 weeks to up to 96 weeks. In some embodiments, the antibody and siRNA are administered for up to 48 weeks. In some embodiments, the antibody and siRNA are administered for up to 72 weeks. In some embodiments, the antibody and siRNA are administered for up to 96 weeks. In some embodiments, the antibody and siRNA are administered every 4 weeks.

[0150] In any of the aforementioned embodiments, the antibody may be administered at a dose of from 200 mg to 400 mg, e.g., 300 mg. In any of the aforementioned embodiments, the siRNA may be administered at a dose of from 100 mg to 300 mg, e.g., 200 mg.V. Example Embodiments

[0151] The following exemplary embodiments are also provided by the present disclosure:1. A method of treating hepatitis D virus (HDV) infection in a subject having a normal ALT level (less than the upper limit of normal) before treatment, the method comprising administering to the subject:75181072933.1(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3 '-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is2. A method of preventing, eliminating, or reducing the number of or frequency of ALT flares in a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and76181072933.1(b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3 -phosphate, 2'-O-methylcytidine-3'-phosphate. 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate. and 2'-fluorouridine-3'-phosphate. respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is3. The method according to embodiment 2. wherein the subject has a normal ALT level (less than the upper limit of normal) before treatment.4. A method of treating a subject having a hepatitis D vims (HDV) infection, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca - 77181072933.13' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL isHO, / 0Hwherein the antibody and siRNA are administered for up to 48 weeks to up to 96 weeks.5. The method according to embodiment 4, wherein the subject has a normal ALT level (less than the upper limit of normal) before treatment.6. The method according to embodiment 4 or embodiment 5, wherein the method further comprises preventing, eliminating, or reducing the number of or frequency of ALT flares in the subject, and / or wherein the method results in prevention, elimination, or reduction of the number of or frequency of ALT flares in the subject.7. A method of treating a subject having a hepatitis D virus (HDV) infection, the method comprising:(1) administering to the subject:78181072933.1(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3 '-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is(2) if the subject has detectable HDV RNA, continuing the administration of step 1, and if the subject does not have detectable HDV RNA, discontinuing the administration of step 1.8. The method according to embodiment 7, wherein a HDV RNA level is determined between step 1 and step 2.79181072933.19. The method according to embodiment 7 or embodiment 8, wherein the administering in step 1 is up to 48 weeks to up to 96 weeks.10. The method according to any one of embodiments 7-9, wherein the subject has a normal ALT level (less than the upper limit of normal) before treatment.11. The method according to any one of embodiments 7-10, wherein the method further comprises preventing, eliminating, or reducing the number of or frequency of ALT flares in the subject, and / or wherein the method results in prevention, elimination, or reduction of the number of or frequency of ALT flares in the subject.12. The method according to any one of embodiments 1-11. wherein the light chain CDRL1, CDRL2, and CDRL3 comprise or consist of the amino acid sequences according to KLGNKN (SEQ ID NO: 12), EVK (SEQ ID NO: 13) or VIYEVKYRP (SEQ ID NO: 14), and QTFDSTTVV (SEQ ID NO: 15), respectively.13. The method according to any one of embodiments 1-12, wherein the heavy chain CDRH1, CDRH2, and CDRH3 comprise or consist of the amino acid sequences according to GRIFRSFY (SEQ ID NO:8), NQDGSEK (SEQ ID NO:9) or INQDGSEK (SEQ ID NO:10), and AAWSGNSGGMDV (SEQ ID NO:11), respectively.14. The method according to any one of embodiments 1-13, wherein the light chain variable domain (VL) comprises or consists of the amino acid sequence according to SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYEVKYRP SGIPERFSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVL(SEQ ID NO:17).15. The method according to any one of embodiments 1-14, wherein the heavy chain variable domain (VH) comprises or consists of the amino acid sequence according to ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATIN QDGSEKLYVDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSG GMDVWGQGTTVSVSS (SEQ ID NO:16).16. The method according to any one of embodiments 1-15. wherein the L is conjugated to the siRNA as shown in the following structure:80181072933.13'wherein X is O.17. The method according to any one of embodiments 1-16, wherein the antibody and siRNA are administered for up to 48 weeks.18. The method according to any one of embodiments 1-16. wherein the antibody and siRNA are administered for up to 72 weeks.19. The method according to any one of embodiments 1-16, wherein the antibody and siRNA are administered for up to 96 weeks.20. The method according to any one of embodiments 1-19, wherein the antibody and siRNA are administered every 4 weeks.21. The method according to any one of embodiments 1-20, wherein the antibody and siRNA are administered subcutaneously.22. The method according to any one of embodiments 1-21, wherein the antibody is administered at a dose of from 200 mg to 400 mg.23. The method according to embodiment 22, wherein the antibody is administered at a dose of 300 mg.24. The method according to any one of embodiments 1-23, wherein the siRNA is administered at a dose of from 100 mg to 300 mg.25. The method according to embodiment 24, wherein the siRNA is administered at a dose of 200 mg.81181072933.126. The method according to any one of embodiments 1-25, wherein the subject has non-cirrhotic or compensated cirrhotic liver disease.27. An anti-HBV antibody; and an siRNA that targets an HBV mRNA; for use in the method according to any one of embodiments 1-26.28. An anti-HBV antibody for use in the method according to any one of embodiments 1-26; wherein the subject is also administered an siRNA that targets an HBV mRNA.29. An siRNA that targets an HBV mRNA for use in the method according to any one of embodiments 1-26; wherein the subject is also administered an anti-HBV antibody.30. Use of an anti-HBV antibody; and an siRNA that targets an HBV mRNA; in the manufacture of a medicament for use in the method according to any one of embodiments 1-26.31. Use of an anti-HBV antibody in the manufacture of a first medicament; and use of an siRNA that targets an HBV mRNA in the manufacture of a second medicament; wherein the first and second medicaments are to be used in a combination therapy according to the method of any one of embodiments 1-26.EXAMPLESEXAMPLE 1CLINICAL EVALUATION OF COMBINATION THERAPY TO TREAT CHRONIC HDV INFECTION

[0152] The safety and efficacy of tobevibart and elebsiran combination therapy are evaluated in a Phase 3, prospective, multicenter, randomized, open-label study clinical study in participants with chronic HDV infection.Summary82181072933.1

[0153] Hepatitis D virus (HDV) is a defective, hepatotropic pathogenic agent dependent on hepatitis B surface antigen (HBsAg) to complete its replication cycle and sustain infection.

[0154] The global prevalence of HDV is estimated to be at least 12 million people. The burden of HDV infection remains high in many African and Asian countries. In Europe and other regions where HBV vaccination was implemented, HDV prevalence in the native population has been diminishing and shifting to older ages. However, HDV is now re-emerging in these regions largely as a result of immigration from endemic regions. HDV prevalence in the US is estimated to be between 65,000 and 100,000 persons, but HDV infection is acknowledged to be underdiagnosed.

[0155] Chronic HDV infection is the most aggressive form of viral hepatitis due to rapid progression to cirrhosis, liver failure, hepatocellular carcinoma (HCC). and death. Results from a recent meta-analysis examining the association between HDV RNA detectability, liver morbidity and mortality showed that persons with detectable HDV RNA were at higher risk of experiencing liver-related events, including developing cirrhosis, HCC and undergoing liver transplantation, and were at higher risk of mortality compared to those with undetectable HDV RNA. Conversely, the loss of detectable HDV RNA is strongly associated with a lower likelihood to experience liver-related complications, and long-term suppression of HDV RNA is associated with more favorable clinical outcomes. HDV viral suppression is the most indicative surrogate marker for improved long-term clinical outcomes in patients with chronic HDV infection.

[0156] The goal of chronic HDV therapy is to reduce HDV RNA to the lowest level possible while normalizing alanine aminotransferase (ALT). However, available treatment options for HDV infection are limited to pegylated-interferon alpha (PEG-IFNa) and in some regions of the world, bulevirtide (BLV). PEG-IFNa treatment establishes a sustained virologic response in ~25 to 30% of patients after 48 weeks of therapy and a similar percentage of patients achieve this response with treatment longer than 48 weeks, but relapses occur in -50% of patients after long-term follow-up. PEG-IFNa is also associated with adverse reactions, the most common of which include flu-83181072933.1like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue and psychiatric sequelae, and is contraindicated in patients with autoimmune diseases, major psychiatric syndromes, and Child-Pugh-Turcotte (CPT)-B or CPT-C stage cirrhosis.

[0157] Bulevirtide, a virus entry inhibitor that targets the sodium taurocholate co-transporting polypeptide (NTCP) receptor, received full approval on 18 July 2023 in the European Union (EU) for treatment of chronic HDV infection. Despite being approved in some countries, access to BLV remains limited and the majority of participants treated with BLV do not achieve undetectable HDV RNA with continued long-term dosing. Additionally, there are a limited number of investigational agents being studied and developed for the treatment of chronic HDV infection and some may have higher incidence of drug intolerability, frequent dosing, and / or drug-drug interactions, further limiting their utility.

[0158] In clinical practice guidelines, nucleoside analogues are indicated for management of chronic HDV infection when control of HBV replication is appropriate. Several studies have reported minimal efficacy of nucleoside analogues either as monotherapy or in combination for treatment of chronic HDV infection. So there continues to be an unmet need for therapies with improved efficacy to achieve and maintain suppression of viremia (HDV RNA < lower limit of quantification [LLOQJ, target not detected [TND]).

[0159] Tobevibart and elebsiran are two investigational agents with mechanisms of action targeting HBsAg at different steps in the HDV replication cycle. Tobevibart, a monoclonal antibody (mAb) targeting the antigenic loop of HBsAg, prevents viral entry and complexes circulating HBsAg to neutralize virions. Elebsiran is a synthetic, chemically modified siRNA targeting all hepatitis B viral transcripts for degradation, including pgRNA, and is conjugated to a ligand containing 3 N-acetyl galactosamine (GalNAc) residues to facilitate delivery to the liver. Preliminary data from the SOLSTICE trial suggest tobevibart+elebsiran has the potential to fulfill this unmet need by providing an efficacious, well tolerated, and more convenient therapeutic option for patients.84181072933.1

[0160] This study will evaluate the efficacy of tobevibart+elebsiran combination therapy in participants with chronic HDV infection. The primary efficacy objective is to evaluate the ability of 48 weeks of tobevibart+elebsiran combination therapy compared to 12 weeks of delayed treatment in achieving HDV RNA < LLOQ, TND and normalizing ALT. The key secondary efficacy endpoint is HDV RNA < LLOQ, TND at Week 48 in Arm 1 versus at Week 12 in Arm 2. The primary safety objective is to evaluate the safety of tobevibart+elebsiran combination therapy. This study will also assess the long-term impact of HDV RNA suppression on liver fibrosis progression, cirrhosis, decompensated liver disease, hepatic impairment, liver transplantation. HCC and liver-related death in participants with chronic HDV infection through 240 weeks of combination therapy.Background and Rationale

[0161] HDV, also known as hepatitis delta virus, is a defective, hepatotropic pathogenic agent. The genome is a circular, single-stranded RNA of approximately 1700 nucleotides which only codes for the hepatitis delta antigen. HDV relies on HBsAg to complete its replication cycle, including viral packaging, infectivity, transmission, and inhibition of host immunity. HDV virions can be assembled using HBsAg derived from cccDNA as well as from integrated HBV in hepatocytes (Freitas 2014; Shirvani-Dastgerdi 2015).

[0162] The prevalence of HDV is estimated to be at least 12 million people worldwide (Chen 2019; Miao 2020; Stockdale 2020). A recent literature review undertaken by the Polaris Observatory Collaborators estimated the prevalence of HDV in 25 countries and territories. Estimates ranged widely between countries, from 0.2% in Hong Kong and Mexico to 61.0% in Mongolia, with the overall prevalence among HBsAg positive persons being 2%. The burden of HDV infection remains high in many African and Asian countries. In Europe and other regions where HBV vaccination was implemented, HDV prevalence in the native population has been diminishing and shifting to older ages. However, HDV is now re-emerging in these regions largely as a result of immigration from areas where HDV remains endemic. HDV prevalence in the US is estimated to be between 65,000 and 100,000 persons, but HDV infection is85181072933.1acknowledged to be underdiagnosed (POC 2024; POC 2023; Stockdale 2020). Factors contributing to HDV underdiagnosis include variation in awareness and incomplete testing among people who are HBsAg positive, issues with standardization of confirmatory molecular diagnostic techniques, and a historical lack of effective treatment options even in high-income settings.

[0163] Chronic HDV infection is the most aggressive form of viral hepatitis due to rapid progression to cirrhosis and end stage liver disease including liver failure, HCC and death (Lee 2021; Stockdale 2020). Among persons with chronic HDV infection, 85% to 95% may develop cirrhosis and liver failure within 10 years of infection with approximately 15% developing these complications as early as 1 to 2 years after infection (Kamili 2017; Rizzetto 2015a; WHO 2023). Notably, approximately 50% of HDV infected patients are cirrhotic at diagnosis (Fattovich 1987). HDV viremia has been shown to be a major driver of progression to cirrhosis and / or liver decompensation, and development of HCC (Palom 2020; Romeo 2014). The risk for liver-related events and development of HCC has been found to be 3.8-fold and 2.6-fold higher, respectively, in patients with HDV viremia versus patients without HDV viremia (Kamal 2020). Results from a recent meta-analysis examining the association of HDV RNA detectability and liver morbidity and mortality also showed that patients with detectable HDV RNA were 7 times more likely to undergo liver transplantation and were at higher risk of mortality compared to those with undetectable HDV RNA (Gish 2024). Conversely, the loss of detectable HDV RNA is strongly associated with a lower likelihood to experience liver-related complications, and long-term suppression of HDV RNA is associated with more favorable clinical outcomes (Wranke 2017; Wranke 2020). HDV viral suppression is the most indicative surrogate marker for improved long-term clinical outcome in patients with chronic HDV infection.

[0164] The goal of chronic HDV therapy is to reduce HDV RNA to the lowest level possible while normalizing ALT. However, available treatment options for HDV infection remain limited.

[0165] For more than 30 years, the only available treatment for HDV infection was PEG-IFNa; however, it is not approved for this indication (EASL 2017; Sarin86181072933.12016; Terrault 2018). PEG-IFNa treatment establishes a sustained virologic response (clearance of serum HDV RNA after stopping treatment) in around 25 to 30% of patients after 48 weeks of therapy and a similar percentage of patients achieve this response with treatment longer than 48 weeks (Wedemeyer 2011). However, relapses occur in -50% of patients after long-term follow-up (Heidrich 2014). PEG-IFNa is also associated with adverse reactions (eg, flu-like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue and psychiatric sequelae), which persist as long as patients are on treatment, and is contraindicated in patients with autoimmune diseases, major psychiatric syndromes, and CPT-B or CPT-C stage cirrhosis (Rizzetto 2015b; Sleijfer 2005).

[0166] BLV, a virus entry inhibitor that targets the NTCP receptor, received full marketing authorization on 18 July 2023 in the EU for treatment of chronic HDV infection (EMEA / H / C / 004854 / II / 0019) (EMA 2023). Despite being approved in some countries, access to BLV remains limited and the majority of participants treated with BLV do not achieve undetectable HDV RNA with continued long-term dosing (Wedemeyer 2023a). Additionally, there are a limited number of investigational agents being studied and developed for the treatment of chronic HDV infection and some may have higher incidence of drug intolerability, frequent dosing, and / or drug-drug interactions, further limiting their utility.

[0167] In clinical practice guidelines, nucleoside analogues are indicated for chronic HDV management when control of HBV replication is appropriate; EASL practice guidelines recommend nucleoside analogues in patients with active HBV replication or when prevention of reactivation of HBV is clinically important such as in decompensated patients and patients with compensated cirrhosis and detectable serum HBV DNA (EASL 2023). The AASLD guidance endorses entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide to suppress HBV replication and treat patients with chronic HDV infection who have elevated HBV DNA levels (Terrault 2018). However, several studies have reported minimal efficacy of nucleoside analogues either as monotherapy or in combination for treatment of chronic HDV infection.87181072933.1

[0168] There continues to be an unmet need for therapies with improved efficacy to achieve and maintain suppression of viremia (HDV RNA < LLOQ, TND). The Sponsor is evaluating 2 investigational agents targeting HBsAg at different steps in the HDV replication cycle as potential therapeutics to achieve durable suppression of HDV viremia and reduce incidence of end stage liver disease outcomes.

[0169] Tobevibart is an Fc engineered, human IgGl mAb targeting the antigenic loop of HBsAg. Tobevibart acts as an HDV entry inhibitor by blocking interactions between HBsAg on the surface of virions and the cellular receptor(s) on hepatocytes thus preventing viral entry’. Tobevibart can also form immune complexes with free and viral associated HBsAg leading to opsonization and elimination of HDV virions from the blood stream. In in vitro experiments, tobevibart completely blocked viral entry and consequently HDV infection in Huh7-NTCP cells.

[0170] Elebsiran is a synthetic, chemically modified siRNA targeting all HBV viral transcripts for degradation and is conjugated to a ligand containing GalNAc residues to facilitate delivery to the liver. By reducing HBsAg production, elebsiran interferes with the production of infectious HDV virions. In in vitro experiments, treatment of HBV / HDV co-infected primary human hepatocytes with elebsiran led to a dose-dependent reduction of secreted infectious HDV virions.

[0171] The Phase 2 SOLSTICE study was designed to evaluate the safety and efficacy of tobevibart and elebsiran as monotherapies and in combination in noncirrhotic and compensated cirrhotic participants with chronic HDV infection on NRTI therapy (NCT05461170 2022). In a preliminary analysis, in the tobevibart+elebsiran Q4W de novo cohort (Cohort 2C de novo), all participants (n=32) who have reached Week 24 have achieved a virologic response (HDV RNA < LOD or > 2 log10 decline from baseline in HDV RNA), with 40.6% (13 of 32) of participants achieving undetectable HDV RNA (HDV RNA < LLOQ, TND); 46.9% (15 of 32) of participants achieving ALT normalization; and 18.8% (6 of 32) of participants achieving undetectable HDV RNA and ALT normalization (Asselah 2024). In the tobevibart monotherapy Q2W cohort (Cohort 3), 33 participants reached Week 24 and 81.8% (27 of 33) of participants achieved a virologic response, with 30.3% (10 of 33)88181072933.1achieving undetectable HDV RNA; 75.8% (25 of 33) of participants achieving ALT normalization; and 21.2% (7 of 33) achieving undetectable HDV RNA and ALT normalization. ALT flares have not been observed thus far in Cohorts 2c de novo and 3; most AEs reported have been transient and mild / moderate in severity and no treatment-related SAEs have been reported.

[0172] Preliminary clinical efficacy data from the SOLSTICE study for treatment of chronic HDV infection demonstrated that participants treated with tobevibart+elebsiran Q4W achieve HDV RNA LLOQ, TND at Week 24 while normalizing ALT. Therefore, combination therapy of tobevibart and elebsiran has the potential to address significant unmet need by providing an efficacious and more convenient therapy than daily SC administration with transient mild / moderate AEs.

[0173] Despite BLV being established as the standard of care in many regions, BLV remains inaccessible to all eligible patients and is not approved in many countries, and a large proportion of patients with HDV do not achieve complete HDV suppression on this drug. Additionally, some patients are unable or unwilling to tolerate daily SC injections. Thus, an unmet medical need exists for anti-HDV therapies with greater efficacy leading to sustained suppression of viremia as well as less frequent administration.

[0174] This study will evaluate the efficacy of immediate versus delayed treatment with tobevibart+elebsiran. In this study, participants on NRTI therapy active against HBV will be randomized to start tobevibart+elebsiran on Day 1 (Arm 1) or delay treatment with tobevibart+elebsiran for 12 weeks while remaining on NRTI (Arm 2). The primary efficacy endpoint is HDV RNA < LLOQ, TND and ALT normalization (ALT < ULN) at Week 48 for Arm 1 vs at Week 12 for Arm 2. The key secondary efficacy endpoint is HDV RNA < LLOQ, TND at Week 48 in Arm 1 versus at Week 12 in Arm 2. Additional efficacy assessments include assessing the impact of tobevibart+elebsiran on liver fibrosis, and serious clinical outcomes including progression to cirrhosis, HCC, liver transplantation and liver-related mortality through 240 weeks of tobevibart+elebsiran study intervention. Safety of tobevibart+elebsiran will also be assessed.89181072933.1Benefit Assessment and Objectives

[0175] HDV viremia is strongly associated with progression to cirrhosis (in patients with or without ALT elevations), HCC, liver transplantation and liver-related mortality. Most patients on current therapies do not achieve undetectable HDV RNA and normalization of ALT. Additionally, there are a limited number of investigational agents being studied and developed for the treatment of chronic HDV infection, and some may have higher incidence of drug intolerability, frequent dosing, and / or drugdrug interactions, further limiting their utility. There continues to be an unmet need for therapies with improved efficacy to achieve and maintain suppression of viremia (HDV RNA < LLOQ, TND) and normalization of ALT, leading to improved clinical outcomes. HDV is dependent upon HBsAg to form infectious virions, therefore decreasing or eliminating HBsAg expression is expected to inhibit the formation of nascent HDV virions and ultimately reduce HDV viremia. Efficacy data from clinical studies in participants with chronic HBV provide proof of concept of the mechanism of action of tobevibart and elebsiran in reducing HBsAg (see Lim 2022; Agarwal 2021; Agarwal 2022b). In study VIR-2218-1006, coadministration of elebsiran and tobevibart is associated with a reduction of HBsAg (Gane 2022); the pattern of decline seen in this study is indicative of an additive effect of elebsiran and tobevibart combination therapy.

[0176] Preliminary clinical efficacy data from the SOLSTICE study for treatment of chronic HDV infection demonstrate tobevibart+elebsiran combination therapy is associated with HDV RNA suppression, including achieving undetectable HDV RNA, and ALT normalization in noncirrhotic and compensated cirrhotic participants (Asselah 2024).

[0177] Sustained viral suppression (HDV RNA < LLOQ, TND) has also been observed once viral suppression is achieved, with no rebound in HDV RNA observed (Asselah 2024). ALT flares previously observed with siRNA therapies alone had not been seen with administration of tobevibart+elebsiran to date (Asselah 2023; see also Wedemeyer 2023c) and no significant safety findings have been identified.

[0178] Preliminary clinical efficacy data from the SOLSTICE study for treatment of chronic HDV infection suggest that a combination regimen of90181072933.1tobevibart+elebsiran Q4W, by suppressing viremia (HDV RNA < LLOQ, TND), has the potential to fulfill this unmet need by providing an efficacious therapy with less frequent dosing that may reduce the likelihood of progression to serious clinical outcomes including cirrhosis, hepatic decompensation, HCC and death.

[0179] Study objectives and endpoints are shown in Table 3. HDV RNA < LLOQ. TND refers to HDV RNA < 63 lU / mL (LLOQ of the assay).Table 3, Study objectives and associated endpoints.Objectives EndpointsTo evaluate the efficacy of HDV RNA < LLOQ, TND and ALT tobevibart+elebsiran compared with normalization (ALT < ULN) at Week delayed treatment in participants with 48 for Arm 1 vs at Week 12 for Arm 2 chronic HDV infectionT o evaluate the antiviral effect of HDV RNA < LLOQ, TND at Week 48 tobevibart+elebsiran on HDV viremia for Arm 1 vs at Week 12 for Arm 2 compared with delayed treatment in (key secondary endpoint) participants with chronic HDVinfection HDV RNA < LLOQ at Week 48 for Arm 1 vs at Week 12 for Arm 2 Change from baseline in HDV RNA at Week 48 for Arm 1 vs at Week 12 for Arm 2To evaluate the impact of ALT < ULN at Week 48 for Arm 1 vs tobevibart+elebsiran on ALT at Week 12 for Arm 2compared with delayed treatment inparticipants with chronic HDV ALT < 1.25 x ULN at Week 48 for infection Arm 1 vs at Week 12 for Arm 2Change from baseline in ALT at Week 48 for Arm 1 vs at Week 12 for Arm 2To evaluate the efficacy of HDV RNA < LLOQ, TND and ALT < tobevibart+elebsiran compared with 1.25 x ULN at Week 48 for Arm 1 vs delayed treatment in participants with at Week 12 for Arm 2chronic HDV infectionTo evaluate the long-term efficacy of HDV RNA < LLOQ, TND and ALT < tobevibart+elebsiran in participants ULN at 48, 96, 144, 192, and 240 with chronic HDV infection weeks of tobevibart+elebsirantreatment91181072933.1HDV RNA < LLOQ and ALT < ULN at 48, 96, 144, 192, and 240 weeks of tobevibart+elebsiran treatment HDV RNA < LLOQ, TND and ALT < 1.25 x ULN at 48, 96, 144, 192, and 240 weeks of tobevibart+elebsiran treatmentTo evaluate the long-term antiviral HDV RNA < LLOQ, TND at 48, 96, effect of tobevibart+elebsiran on HDV 144, 192, and 240 weeks of viremia in participants with chronic tobevibart+elebsiran treatment HDV infectionHDV RNA < LLOQ at 48, 96, 144, 192, and 240 weeks of tobevibart+elebsiran treatment Change from baseline in HDV RNA at 48, 96, 144, 192, and 240 weeks of tobevibart+elebsiran treatment To evaluate the long-term impact of ALT < ULN at 48, 96, 144, 192, and tobevibart+elebsiran on ALT in 240 weeks of tobevibart+elebsiran participants with chronic HDV treatmentinfectionALT < 1.25 x ULN at 48, 96, 144, 192, and 240 weeks of tobevibart+elebsiran treatment Change from baseline in ALT at 48, 96, 144, 192, and 240 weeks of tobevibart+elebsiran treatment To evaluate the long-term impact of Change from baseline in liver tobevibart+elebsiran on liver stiffness stiffness as measured by liver in participants with chronic HDV elastography at 48, 96, 144, 192, and infection 240 weeks of tobevibart+elebsiran treatmentTo evaluate the impact of Incidence of decompensated tobevibart+elebsiran on end stage cirrhosis (clinical event or CPT score liver disease outcomes in participants > 7) by 48, 96, 144, 192, and 240 with chronic HDV infection weeks of tobevibart+elebsiran treatmentIncidence of HCC and progression to liver failure requiring transplantation or resulting in death by 48, 96, 144, 192, and 240 weeks oftobevibart+elebsiran treatment92181072933.1To evaluate the safety of Incidence of TEAEs and SAEs tobevibart+elebsiran in participants through Week 12with chronic HDV infectionTo evaluate the safety of Incidence of TEAEs and SAEs tobevibart+elebsiran in participants through 48, 96, 144, 192, and 240with chronic HDV infection weeks of treatmentStudy Design

[0180] This Phase 3, prospective, multicenter, randomized, parallel-arm, openlabel study will investigate immediate treatment with tobevibart+elebsiran compared to 12-week delayed treatment followed by tobevibart+elebsiran in adult participants > 18 years with chronic HDV infection on nucleos(t)ide reverse transcriptase inhibitor (NRTI) therapy active against hepatitis B virus (HBV).

[0181] The study will enroll participants with chronic HDV infection with elevated ALT who are noncirrhotic (with any level of liver fibrosis) or have compensated cirrhosis (CPT-A). Participants will be randomized 2: 1 to receive immediate treatment with tobevibart+elebsiran SC (subcutaneously) Q4W for 240 weeks (Arm 1), or 12-week delayed treatment followed by tobevibart+elebsiran SC Q4W (every 4 weeks) for 240 weeks (Arm 2). The randomization will be stratified by presence of cirrhosis (noncirrhotic or compensated cirrhotic). Up to approximately 50% of participants enrolled into the study will have compensated cirrhosis (CPT-A).

[0182] Eligible participants include adult male and nonpregnant, nonlactating females aged > 18 to < 70 years with positive HDV antibody for at least 6 months, HDV RNA > 500 lU / mL, elevated ALT and on NRTI therapy active against HBV.

[0183] The purpose of the study is to evaluate the efficacy and safety of immediate versus delayed treatment with tobevibart+elebsiran combination therapy. The rimary efficacy endpoint is HDV RNA virologic suppression (defined as HDV RNA < LLOQ, TND) and ALT normalization (ALT < ULN) at Week 48 for Arm 1 versus at Week 12 for Arm 2.

[0184] Approximately 120 participants will be enrolled into the study in several countries. Participants will be randomized in a 2: 1 ratio to receive immediate treatment with tobevibart+elebsiran or delayed treatment.93181072933.1

[0185] Intervention groups include: Arm 1: tobevibart+elebsiran SC Q4W starting at Day 1: and Arm 2: tobevibart+elebsiran SC Q4W starting at Week 12. The total study duration for Arm 1 participants is planned to be up to 270 weeks total. This includes a 6-week screening period, followed by up to 240 weeks of the study intervention treatment period and a 24-week follow-up period for participants not continuing to receive tobevibart+elebsiran after completion of study intervention in this study. The total study duration for Arm 2 participants is planned to be up to 282 weeks, including a 6-week screening period, a 12- week observational period on NRTIs, followed by up to 240 weeks of the study intervention treatment period and a 24-week follow-up period for participants not continuing to receive tobevibart+elebsiran after completion of study intervention in this study.

[0186] All participants will receive up to 240 weeks of tobevibart+elebsiran; participants who are randomized to Arm 1 will receive the first dose on Day 1 and participants who are randomized to Arm 2 will receive the first dose of tobevibart+elebsiran on Week 12, after an observational period on NRTIs.

[0187] Tobevibart is provided as a reconstituted lyophilized powder administered subcutaneously (SC) at 300 mg every 4 weeks. Elebsiran is provided as a liquid administered SC at 200 mg every 4 weeks.

[0188] The study schema is shown is shown in Figure 1. Table 4 shows the treatment / intervention groups. Figures 2A-2C show the Schedule of Activities for the study inters ention treatment period with tobevibart+elebsiran (Screen to Week 48 for Arm 1; Week 12 to Week 60 for Arm 2). Figures 3A-3C show the Schedule of Activities for the study intervention treatment period with tobevibart+elebsiran (Week 52 to Week 240 for Arm 1; Week 64 to Week 252 for Arm 2). Figures 4A-4B show the Schedule of Activities for the delayed treatment period (Screen to W8 for Arm 2). Figure 5 shows the Schedule of Activities for the Follow-Up Period (Arm 1 and Arm 2).Table 4, Treatment groups for clinical study.Arm Intervention Dose Route Number ScheduleGroup of Doses94181072933.11 tobevibart+ 300 mg SC Up to 60 Every 4 elebsiran tobevibart weeks, starting at 200 mg elebsiran day 1 2 delayed 300 mg SC Up to 60 Every 4 treatment of tobevibart weeks, tobevibart+ starting atelebsiran 200 mg elebsiran Week 12 SC=subcutaneousParticipant Population

[0189] Participants include adult male and nonpregnant, nonlactating females aged > 18 to < 70 years with chronic HDV infection, both noncirrhotic and cirrhotic up to METAVIR-F4 / CPT-A, currently on NRTI therapy. Participants who fulfill the following inclusion and exclusion criteria at screening are eligible for participation in this study.

[0190] Inclusion criteria include the following:1) Adult men and women aged > 18 years (or age of legal consent, whichever is older) to < 70 years at the time of signing informed consent2) Positive HDV antibody or positive HDV RNA PCR result for at least 6 months prior to screening and HDV RNA > 500 IU / mL at screening.3) Noncirrhotic or compensated cirrhotic liver disease (up to approximately 50% of participants enrolled will be CPT-A cirrhotic) at screening.o Noncirrhotic as defined by liver biopsy with METAVIR F0-F3 or liver stiffness (as measured by elastography, e.g., FibroScan®, see Afdhal 2012) < 15 kPa within the 12 months prior to or at screening.o Compensated cirrhotic as defined by meeting all criteria below:i. Liver biopsy with METAVIR F4 or liver stiffness (as measured by elastography, e.g., FibroScan®) > 15 and < 25 kPa within the 12 months prior to or at screeningii. CPT score of 5 or 6, inclusive at screeningiii. Compensated liver disease based on Investigator assessment The Child-Pugh Turcotte (CPT) Score Assessment of Liver Disease is shown in Table 5.95181072933.1Table 5, Child-Pugh Turcotte (CPT) Score Assessment of Liver Disease.Points Scored for Observed Findings1 2 3 Encephalopathy grade* None 1 or 2 3 or 4Ascites Absent slight moderate (diuretic (diuretic responsive) unresponsive)Serum bilirubin, mg / dL <2 2 to 3 >3Serum albumin, g / dL >3.5 2.8 to 3.5 <2.8 Prothrombin time, sec <4 4 to 6 >6prolonged*Grade 0: normal consciousness, personality, neurological examination electroencephalogramGrade 1: restless, sleep disturbed, irritable / agitated, tremor, impaired handwriting, 5 cycle per second wavesGrade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic wavesGrade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower wavesGrade 4: unrousable coma, no personahty / behavior, decerebrate, slow 2-3 cycle per second delta activity7Source: FDA 2003Assessment: Class A (mild hepatic impairment) if 5 or 6 points; B (moderate hepatic impairment) if 7 to 9 points; and C (severe hepatic impairment) if 10 to 15 points.4) Serum ALT > ULN and < 5 x ULNULN values for ALT may be, for example, 34 lU / rnL for females and 43 lU / mL for males.5) BMI > 18 kg / m2to < 40 kg / m26) On NRTI therapy against HBV for at least 12 weeks prior to Day 1 or have HBV DNA < 20 lU / ml at screening, and currently on locally approved NRTI therapy. Participants must be on one of the following NRTI therapies: tenofovir alafenamide (taken alone or as part of fixed-dose combination therapy), tenofovir disoproxil fumarate (taken alone or as part of fixed-dose combination therapy), or entecavir.96181072933.17) Participants with hepatic impairment with co-morbid diseases requiring medication(s) must be taking the medication(s) without a change in dose for > 3 months prior to screening. All concomitant medications must be approved by the CRO Medical Monitor prior to study enrollment.8) 12-lead ECG within normal limits; or, with no clinically significant abnormalities at screening, as determined by the Investigator.

[0191] Exclusion criteria include the following:1) Current or prior history of any of the following:i. Clinically significant laboratory abnormalities, co-morbid medical condition (other than HBV / HDV coinfection) or planned medical procedure that may interfere with the participant's treatment, assessment, or compliance with the protocol. Participants under evaluation for a potentially clinically significant illness (other than HBV / HDV coinfection) are also excluded.ii. Difficulty with blood collection and / or poor venous access for the purposes of phlebotomy.iii. Current or previous (within 24 months of screening) clinically identified hepatic decompensation (eg, coagulopathy, hyperbilirubinemia, hypoalbuminemia, ascites, encephalopathy, variceal hemorrhage, hepalopulmonary or hepatorenal syndrome) or liver disease requiring paracentesis > 1 time per month or managed with Transjugular Intrahepatic Portosystemic Shunt placement.iv. Bone marrow, peripheral blood stem-cell or solid organ transplantation v. Psychiatric hospitalization, suicide attempt, and / or a period of disability as a result of their psychiatric illness within the last 5 years. Participants with psychiatric illness that is well-controlled on a stable treatment regimen for at least 12 months prior to randomization or has not required medication in the last 12 months may be included.vi. Malignancy diagnosed or treated within 5 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; ductal97181072933.1carcinoma in situ and cervical carcinoma in situ is allowed if appropriately treated prior to screening); participants under evaluation for malignancy are not eligible.vii. Significant drug allergy (such as anaphylaxis or hepatotoxicity)2) One or more additional known primary or secondary causes of liver disease, other than hepatitis B or hepatitis D (i.e., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, Wilson’s disease, other congenital or metabolic condition affecting the liver, congestive heart failure, etc).3) History of clinically significant immune complex disease.4) History of anaphylaxis, allergic reactions, hypersensitivity, or intolerance to study drug, its metabolites or excipients5) Participants with active HCV (participants with HCV antibodies can be enrolled if screening HCV RNA PCR test is negative).6) Participants with HIV infection (participants with HIV infection can be enrolled if CD4+ T-cell counts are > 500 / mm3and HIV RNA PCR is below the limit of detection for at least 12 months).7) Participants with HAV (participants who are HAV IgM positive can be enrolled if asymptomatic and HAV IgG positive).8) Participants with HEV (participants who are HEV IgM positive can be enrolled if asymptomatic and HEV IgG positive). In cases where acute infection status cannot be determined by serologies a serum or stool HEV RT-PCR can be obtained. The participant is ineligible if PCR is positive.9) Current therapy or therapy within 24 weeks of first study intervention administration with an immunomodulatory agent (eg, IFN-a), immune checkpoint inhibitors, immunosuppressants (eg, disease-modifying antirheumatic drugs), cytotoxic or chemotherapeutic agent, or chronic systemic corticosteroids (equivalent of 10 mg prednisone QD).10) Receipt of an investigational or approved HDV antiviral (eg, lonafamib, antisense oligonucleotide, IFN-lambda, BLV) within 24 weeks or 5 half-lives (if98181072933.1know n), whichever is longer, of first study intervention administration or are active in the follow-up period of another clinical study involving interventional HDV treatment.11) Participants must agree not to take part in any other investigational study at any time during their participation in this study, inclusive of the follow-up period. 12) Receipt of elebsiran or any siRNA targeting HBV or HDV within 24 weeks of first study intervention administration or experienced an ALT flare (ALT > 5 / ULN) while receiving an anti-HBV or HDV siRNA.13) Receipt of tobevibart or any antibody targeting HBV or HDV within 24 weeks or 5 half-lives (if known), whichever is longer, of first study intervention administration.14) Participants with the following laboratory’ parameters at screening:i. ALT > 5 x ULNii. Total bilirubin > 2.0 mg / dLiii. Serum albumin < 28 g / Liv. Platelet count < 60 x 10A3 / p. Lv. INR> 1.5vi. CrCl < 30 rnL / min as estimated using Cockcroft-Gault formulavii. WBC Differential, Neutrophils < 1.0 x 10^3 / μL15) History or clinical evidence of alcohol or drug abuse within 6 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). Cannabis use is permitted.

[0192] The following concomitant therapies are not permitted during the study: 1) Participants must abstain from taking prescription drugs outside the care of a prescribing physician and nonprescription drugs (including vitamins, recreational drugs, and dietary or herbal supplements) within 7 days or 5 half-lives (whichever is longer) before the start of study intervention until completion of99181072933.1the follow-up visits, unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the study.2) Use of any of the following systemic medications is prohibited within 24 weeks before study intervention administration and throughout the study: Chronic systemic steroids (prednisone equivalent of > 10 mg / day) or other immunosuppressive agents (Note: corticosteroid administration for the treatment of immune-mediated AEs and short courses of corticosteroids for chronic obstructive pulmonary disease or asthma exacerbations is allowed)3) Additionally, the administration of any potentially hepatotoxic medications during the study should be considered only if no therapeutic alternative can be identified and after a careful consideration of the potential risks and benefits for the participant. Medications that are potentially hepatotoxic or associated with drug-induced liver injury include, but are not limited to, the following (Bjornsson 2016): Paracetamol (acetaminophen) > 3 g / day, Aspirin > 3 g / day or ibuprofen > 1.2 g / day, Tricyclic antidepressants, Valproate. Phenytoin, Amiodarone.Anabolic steroids, Allopurinol, Amoxicillin-clavulanate, Minocycline, Nitrofurantoin, Sulfamethoxazole / trimethoprim, Erythromycin. Rifampin, Isoniazid, Azole antifungals, Herbal or natural remediesReferences

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[0222] NCT05461170. A Phase 2 Study to Evaluate Efficacy, Safety and Tolerability’ of VIR-2218 and VIR-3434 in Participants With Chronic Hepatitis D Virus Infection (SOLSTICE). Vir Biotechnology, Inc. Vir Biotechnology, Inc., 2022. Facility: N / A. Available from: clinicaltrials.gov / study / NCT05461170

[0223] Palom, A., Rodriguez-Tajes, S., Navascues, C. A., et al. Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia. Aliment Pharmacol Ther. 2020;51(l) 158-66 Epub 20191113. doi: 10.1111 / apt.15521. PubMed PMID: 31721254104181072933.1

[0224] POC. Adjusted estimate of the prevalence of hepatitis delta virus in 25 countries and territories. J Hepatol. 2024;80(2) 232-42 Epub 20231127. doi:10.1016 / j.jhep.2023.10.043. PubMed PMID: 38030035

[0225] POC. Global prevalence, cascade of care, and prophylaxis coverage of hepatitis B in 2022: a modelling study. Lancet Gastroenterol Hepatol. 2023;8(10) 879-907 Epub 20230727. doi: 10.1016 / S2468-1253(23)00197-8. PubMed PMID: 37517414

[0226] Rizzetto, M. Hepatitis D Virus: Introduction and Epidemiology. Cold Spring Harb Perspect Med. 2015a;5(7) a021576 Epub 20150701. doi:10.1101 / cshperspect.a021576. PubMed PMID: 26134842 PubMed Central PMCID: PMC4484953

[0227] Rizzetto, M., Smedile, A. Pegylated interferon therapy of chronic hepatitis D: in need of revision. Hepatology. 2015b;61 (4) 1109-11 Epub 20150309. doi: 10.1002 / hep.27585. PubMed PMID: 25348580

[0228] Romeo, R., Foglieni, B., Casazza, G., et al. High serum levels of HDV RNA are predictors of cirrhosis and liver cancer in patients with chronic hepatitis delta. PLoS One. 2014;9(3) e92062 Epub 20140321. doi: 10.1371 / joumal.pone.0092062. PubMed PMID: 24658127 PubMed Central PMCID: PMC3962389

[0229] Sampson, H. A.. Munoz-Furlong, A., Campbell, R. L., et al. Second symposium on the definition and management of anaphylaxis: summary report-Second National Institute of Allergy and Infectious Disease / Food Allergy' and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2) 391-7. doi:10.1016 / j.jaci.2005.12.1303. PubMed Central PMCID: 16461139

[0230] Sarin, S. K., Kumar, M., Lau, G. K., et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016; 10(1) 1-98 Epub 20151113. doi: 10.1007 / s12072-015-9675-4. PubMed PMID: 26563120 PubMed Central PMCID: PMC4722087

[0231] Shirvani-Dastgerdi, E., Tacke, F. Molecular interactions between hepatitis B virus and delta virus. World J Virol. 2015:4(2) 36-41. doi:10.5501 / wjv.v4.i2.36. PubMed PMID: 25964870 PubMed Central PMCID:PMC4419120105181072933.1

[0232] Sleijfer, S., Bannink, M., Van Gool, A. R., et al. Side effects of interferon-alpha therapy. Pharm World Sci. 2005;27(6) 423-31. doi: 10.1007 / s11096-005-1319-7. PubMed PMID: 16341948

[0233] Stockdale, A. J., Kreuels, B., Henrion, M. Y. R., et al. The global prevalence of hepatitis D virus infection: Systematic review and meta-analysis. J Hepatol. 2020:73(3) 523-32 Epub 20200423. doi: 10.1016 / j.jhep.2020.04.008. PubMed PMID: 32335166 PubMed Central PMCID: PMC7438974

[0234] Terrault, N. A., Lok, A. S. F., McMahon, B. J., et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4) 1560-99. doi: 10.1002 / hep.29800. PubMed PMID: 29405329 PubMed Central PMCID: PMC5975958

[0235] Wedemeyer, H., Aleman. S., Brunetto. M.. et al. Efficacy and safety at 96 weeks of bulevirtide 2 mg or 10 mg monotherapy for chronic hepatitis D (CHD): results from an interim analysis of a pphase 3 randomized study. (Oral OS-068). In: Vir Biotechnology Inc., editor. In: EASE; June 21-24,; Vienna, Austria. N / A: The International Liver Congress: European Association for the Study of the Liver 2023a: p.28.

[0236] Wedemeyer, H., Aleman. S., Brunetto, M. R., et al. A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D. N Engl J Med. 2023b;389(1) 22-32 Epub 20230622. doi: 10.1056 / NEJMoa2213429. PubMed PMID: 37345876

[0237] Wedemeyer, H., Gane, E., Agarwal, K., et al. Treatment with siRNA JNJ-73763989 plus nucleos (t)ide analogue (NA) decreases HBsAg and HDV RNA levels in patients with chronic hepatitis D (CHD): part 1 of the REEF-D study, (abstract: OS-030). In: Janssen, editor. In: EASL; June 23; Vienna (Austria). N / A: The International Liver Congress: European Association for the Study of the Liver 2023c.

[0238] Wedemeyer, H., Yurdaydin, C., Dalekos, G. N., et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364(4) 322-31. doi: 10.1056 / NEJMoa0912696. PubMed PMID: 21268724106181072933.1

[0239] WHO. Hepatitis D Fact Sheet. 2023; Accessed: 16 October 2023; Last Update: 20 July 2023. Available from: www.who.int / news-room / fact-sheets / detail / hepatitis-d

[0240] Wranke. Antiviral treatment and liver-related complications in hepatitis delta. Hepatology. 2017;65(2) 414-25 Epub 20161130. doi: 10.1002 / hep.28876.PubMed PMID: 27770553

[0241] Wranke. Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta. J Viral Hepat. 2020;27(12) 1359-68 Epub 20200811. doi: 10.1111 / jvh.13366. PubMed PMID: 32707605EXAMPLE 2CLINICAL EVALUATION OF COMBINATION THERAPY TO TREAT CHRONIC HDV INFECTION NOT VIROLOGICALLY SUPPRESSED WITH BULEVIRTIDE

[0242] The safety and efficacy of tobevibart and elebsiran combination therapy are evaluated in a Phase 3, randomized, open-label study clinical study in participants with chronic HDV infection not virologically suppressed with bulvirtide.Summary

[0243] Hepatitis D virus (HDV) is a defective, hepatotropic pathogenic agent dependent on hepatitis B surface antigen (HBsAg) to complete its replication cycle and sustain infection.

[0244] Chronic HDV infection is the most aggressive form of viral hepatitis due to rapid progression to liver failure, cirrhosis, hepatocellular carcinoma (HCC), and death. Results from a recent metaanalysis examining the association between HDV RNA detectability, liver morbidity and mortality' showed that persons with detectable HDV RNA were at higher risk of experiencing liver-related events, including developing cirrhosis. HCC and undergoing liver transplantation, and were at higher risk of mortality compared to those with undetectable HDV RNA. Conversely, loss of plasma HDV RNA in HDV seropositive persons is strongly associated with a lower likelihood to experience liver-related complications, and long-term suppression of HDV RNA is associated with more favorable clinical outcomes. Thus, aviremia is the most 107181072933.1indicative marker for improved long-term clinical outcomes in patients with chronic HDV infection.

[0245] Tobevibart is an Fc engineered, human immunoglobulin G1 (IgGl) monoclonal antibody (mAb) targeting the antigenic loop ofHBsAg. Tobevibart acts as an HDV entry inhibitor by blocking interactions between HBsAg on the surface of virions and the sodium taurocholate cotransporting polypeptide (NTCP) receptor on hepatocytes thus preventing viral entry. Tobevibart can also form immune complexes with free and viral associated HBsAg leading to opsonization and elimination of HDV virions from the blood stream. In in vitro experiments, tobevibart completely blocked viral entry and consequently HDV infection in Huh7-NTCP cells.

[0246] Elebsiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting all hepatitis B virus (HBV) viral transcripts for degradation and is conjugated to a ligand containing GalNAc residues to facilitate delivery to the liver. By reducing HBsAg production, elebsiran interferes with the production of infectious HDV virions. In in vitro experiments, treatment of HBV / HDV co-infected primary human hepatocytes with elebsiran led to a dose-dependent reduction of secreted infectious HDV virions.

[0247] Bulevirtide (BLV) is an entry inhibitor of HBV and HDV that targets the NTCP receptor. In the Phase 3 MYR031 study, 45% of participants receiving BLV 2 mg daily (QD) met the primary endpoint (defined as a combined response at Week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 loglO lU / mL from baseline, and normalization of the alanine aminotransferase [ALT] level).However, only 12% (6 of 49) of participants achieved undetectable HDV RNA (< lower limit of quantification [LLOQ], target not detected [TND]) at Week 48, increasing to 20% (10 of 49) at Week 96. Despite continued long-term dosing, approximately 80% of participants do not achieve undetectable HDV RNA. With HDV viremia being strongly associated with progression to cirrhosis (in patients with or without ALT elevations), HCC, liver transplantation and liver-related mortality, there continues to be an unmet need for therapies with improved efficacy to achieve and maintain suppression of viremia (HDV RNA < LLOQ, TND).108181072933.1

[0248] Preliminary clinical efficacy data from the SOLSTICE (VIR-CHDV-V201) study for treatment of chronic HDV infection demonstrate that participants who are treated with tobevibart+elebsiran every 4 weeks (Q4W) achieve HDV RNA < LLOQ, TND by Week 24 and indicate that HDV RNA plasma viremia continues to decline over time. In the tobevibart+elebsiran Q4W de novo cohort (Cohort 2C de novo), 40.6% (13 of 32) of participants achieved HDV RNA < LLOQ, TND through Week 24. Additionally, 5 of 6 (83.3%) participants in the tobevibart+elebsiran Q4W rollover cohort (Cohort 2C rollover) have achieved HDV RNA < LLOQ, TND and have maintained virologic suppression through Week 48. These data suggest tobevibart+elebsiran Q4W therapy is able to suppress and maintain undetectable HDV RNA and has the potential to address an unmet medical need. These data also suggest a high proportion of participants receiving tobevibart+elebsiran may achieve the virologic outcomes associated with sustained virologic response (SVR, defined as maintaining HDV RNA < LLOQ, TND off treatment without any viral blips) and support exploring the proportion of participants who can achieve SVR following interruption of treatment with tobevibart+elebsiran.

[0249] Part 1 of this study will evaluate the efficacy and safety of tobevibart+elebsiran therapy in participants who have not achieved virologic suppression despite receiving BLV 2 mg QD for at least 24 weeks. The primary endpoint is HDV RNA < LLOQ, TND at Week 24 in participants receiving tobevibart+elebsiran versus continuing BLV. In the second part of this study, participants who are randomized to Arm 1 and achieve HDV RNA < LLOQ, TND by Week 48 and maintain suppression through Week 96 on treatment will systematically interrupt tobevibart+elebsiran at Week 96 and be followed through Week 240 for SVR. The primary endpoint for Part 2 of the study is HDV RNA < LLOQ, TND at Week 120 (24 weeks after planned tobevibart+elebsiran treatment interruption).Background and Rationale

[0250] HDV is a defective, hepatotropic pathogenic agent dependent on HBsAg to complete its replication cycle and sustain infection. Chronic HDV infection is the most aggressive form of viral hepatitis due to rapid progression to liver failure,109181072933.1cirrhosis, hepatocellular carcinoma, and death. Results from a recent meta-analysis examining the association between HDV RNA detectability, liver morbidity and mortality showed that persons with detectable HDV RNA were at higher risk of experiencing liver-related events, including developing cirrhosis, HCC and undergoing liver transplantation and were at higher risk of mortality compared to those with undetectable HDV RNA (Palom 2020; Romeo 2014). Conversely, loss of plasma HDV RNA in HDV seropositive persons is strongly associated with a lower likelihood to experience liver-related complications, and long-term suppression of HDV RNA is associated with more favorable clinical outcomes. HDV viral suppression is the most indicative surrogate marker for improved long-term clinical outcomes in patients with chronic HDV infection (Wranke 2020; Wranke 2017).

[0251] Tobevibart is an Fc engineered, human IgGl mAb targeting the antigenic loop of HBsAg. Tobevibart acts as an HDV entry inhibitor by blocking interactions between HBsAg on the surface of virions and the cellular receptor(s) on hepatocytes thus preventing viral entry’. Tobevibart can also form immune complexes with free and viral associated HBsAg leading to opsonization and elimination of HDV virions from the blood stream. In in vitro experiments, tobevibart completely blocked viral entry and consequently HDV infection in Huh7-NTCP cells.

[0252] Elebsiran is a synthetic, chemically modified siRNA targeting all HBV viral transcripts for degradation and is conjugated to a ligand containing GalNAc residues to facilitate delivery to the liver. By reducing HBsAg production, elebsiran interferes with the production of infectious HDV virions. In in vitro experiments, treatment of HBV / HDV co-infected primary human hepatocytes with elebsiran led to a dose-dependent reduction of secreted infectious HDV virions.

[0253] BLV is an entry inhibitor of HBV and HDV that targets the NTCP receptor. Although 45% participants receiving BLV 2 mg QD met the primary endpoint (defined as a combined response at Week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log 10 lU / mL from baseline, and normalization of the ALT level) in the Phase 3 MYR301 study (NCT03852719 2019), only 12% (6 of 49) of participants achieved undetectable HDV RNA (< LLOQ, TND) at Week 48, increasing110181072933.1to 20% (10 of 49) at Week 96 (Wedemeyer 2023a; Wedemeyer 2023b). Despite continued long-term dosing, approximately 80% of participants do not achieve undetectable HDV RNA. With HDV viremia being strongly associated with progression to cirrhosis (in patients with or without ALT elevations), HCC, liver transplantation and liver-related mortality, there continues to be an unmet need for therapies with improved efficacy to achieve and maintain suppression of viremia (HDV RNA < LLOQ, TND).

[0254] Data from Study MYR204 provided proof of concept that patients with chronic HDV who received 96 weeks of treatment with BLV 2 mg QD or BLV 10 mg QD in combination with peg-IFNa can achieve SVR up to 24 and 48 weeks off therapy (Asselah 2024a). Predictors of SVR 48 weeks after the end of treatment included having HDV RNA < LLOQ. TND at the end of treatment with BLV (Week 96) and having HDV RNA < LLOQ, TND at Week 24 on therapy (Zoulim 2024a; Zoulim 2024b). The main driver of participants achieving undetectable HDV RNA in this study is use of peg-IFNa, as significantly more participants who received the combination of peg-IFNa and BLV 10 mg achieved HDV RNA < LLOQ, TND at Week 96 on treatment compared to BLV 10 mg alone (70% vs 22%, respectively), with more participants receiving peg-IFNa and BLV 10 mg achieving SVR after 24 and 48 weeks (46% vs 12%, respectively). As the study has completed, data on longer term sustainability7of off treatment response will not be available, therefore it is unknown whether these participants will experience virologic rebound similar to what has been seen in previous peg-IFNa studies, where approximately 50% of participants relapsed after long-term follow-up (Heidrich 2014).

[0255] The Phase 2 SOLSTICE (VIR-CHDV-V201 ) study was designed to evaluate the safety and efficacy of tobevibart and elebsiran as monotherapies and in combination in noncirrhotic and compensated cirrhotic participants with chronic HDV infection onNRTI therapy for suppression of HBV (NCT05461170 2022). In a preliminary analysis, in the tobevibart+elebsiran Q4W de novo cohort (Cohort 2C de novo), all participants (n=32) who have reached Week 24 have achieved a virologic response (HDV RNA < LOD or > 2 log10 decline from baseline in HDV RNA), with111181072933.140.6% (13 of 32) of participants achieving undetectable HDV RNA (HDV RNA < LLOQ, TND); 46.9% (15 of 32) of participants achieving ALT normalization; and 18.8% (6 of 32) of participants achieving undetectable HDV RNA and ALT normalization (Asselah 2024b). Additionally, 5 of 6 (83.3%) participants in the tobevibart+elebsiran Q4W rollover cohort (Cohort 2C rollover) have achieved HDV RNA < LLOQ. TND and have maintained virologic suppression through Week 48. In the tobevibart monotherapy Q2W cohort (Cohort 3), 33 participants reached Week 24 and 81.8% (27 of 33) of participants achieved a virologic response, with 30.3% (10 of 33) achieving undetectable HDV RNA; 75.8% (25 of 33) of participants normalized ALT; and 21.2% (7 of 33) achieved undetectable HDV RNA and ALT normalization. ALT flares have not been observed in Cohorts 2C de novo and 3; most AEs reported have been transient and mild / moderate in severity and no treatment-related SAEs have been reported.

[0256] Preliminary' clinical efficacy data from the SOLSTICE study for treatment of chronic HDV infection suggest tobevibart+elebsiran Q4W therapy is able to suppress and maintain undetectable HDV RNA and has the potential to address an unmet medical need.

[0257] Part 1 of this study will evaluate the efficacy and safety of tobevibart+elebsiran therapy in participants who have not achieved virologic suppression despite taking BLV 2 mg QD for at least 24 weeks. Participants who have HDV RNA > 500 lU / mL will be randomized (2: 1) to receive tobevibart+elebsiran from Day 1 to Week 24 (Arm 1) or to remain on BLV 2 mg SC QD through Week 24 (Arm 2). The primary' endpoint is HDV RNA < LLOQ, TND at Week 24 in Arm 1 compared to Arm 2. A minimum of 24 weeks duration of treatment with BLV 2 mg prior to Day 1 was chosen to enable an assessment of early virologic response to BLV prior to enrollment and allows a minimum of 48-week duration on treatment with BLV 2 mg at the time of the primary efficacy comparison to tobevibart+elebsiran in the study. This design facilitates assessment of efficacy and safety while allowing for the shortest duration of continuing BLV treatment in participants demonstrating a suboptimal virologic response to BLV therapy prior to switching to tobevibart+elebsiran.112181072933.1

[0258] In Part 2, participants who were randomized to Arm 1 in Part 1 and who achieved and maintained HDV RNA < LLOQ, TND from Week 48 to Week 96 on treatment will systematically interrupt tobevibart+elebsiran at Week 96 and be followed through Week 240 for SVR.

[0259] There are no approved regimens for finite therapy in patients with chronic HDV. Regimens containing peg-IFNa are the only regimens that have demonstrated SVR; however, as described above, long-term durability is low.Additionally, use of peg-IFNa is limited when treating patients with chronic HDV who have cirrhosis and the major adverse reactions and contraindications for this therapy are well described (Gunsar 2005; Rizzetto 2015; Sleijfer 2005).

[0260] Preliminary data from the SOLSTICE study suggests a high proportion of participants receiving tobevibart+elebsiran may achieve the virologic outcomes associated with SVR and support exploring whether participants can achieve SVR following treatment with tobevibart+elebsiran.Benefit Assessment and Objectives

[0261] HDV viremia is strongly associated with progression to cirrhosis (in patients with or without ALT elevations), HCC, liver transplantation and liver-related mortality. Most patients on current therapies do not achieve undetectable HDV RNA and normalization of ALT. Additionally, there are a limited number of investigational agents being studied and developed for the treatment of chronic HDV infection and some may have higher incidence of drug intolerability, frequent dosing, and / or drugdrug interactions, further limiting their utility. There continues to be an unmet need for therapies with improved efficacy to achieve and maintain suppression of viremia (HDV RNA < LLOQ, TND) and normalization of ALT, leading to improved clinical outcomes.

[0262] HDV is dependent upon HBsAg to form infectious virions, therefore decreasing or eliminating HBsAg expression is expected to inhibit the formation of nascent HDV virions and ultimately reduce HDV viremia. Efficacy data from clinical studies in participants with chronic HBV provide proof of concept of the mechanism of action of tobevibart and elebsiran in reducing HBsAg. When dosed as monotherapy in113181072933.1study VIR-2218-1001, 200 mg elebsiran shows reductions in HBsAg, with deeper declines seen in participants who received 6 doses compared with 2 doses (Lim 2022). Monotherapy with 300 mg tobevibart in study VIR-3434-1002 demonstrates the most durable reductions in HBsAg. All participants in this study achieved > 1 log reduction in HBsAg, and a majority also achieved > 1 log reduction in HBV DNA (Agarwal 2021; Agarwal 2022b). In study VIR-2218-1006, coadministration of elebsiran and tobevibart is associated with a reduction of HBsAg (Gane 2022); the pattern of decline seen in this study is indicative of an additive effect of elebsiran and tobevibart combination therapy.

[0263] Preliminary clinical efficacy data from the SOLSTICE study for treatment of chronic HDV infection demonstrate tobevibart+elebsiran combination therapy is associated with HDV RNA suppression, including achieving undetectable HDV RNA and ALT normalization in noncirrhotic and compensated cirrhotic participants (Asselah 2024b). Sustained viral suppression (HDV RNA < LLOQ, TND) has also been observed once viral suppression is achieved, with no rebound in HDV RNA observed (Asselah 2024b). ALT flares previously observed with siRNA monotherapies had not been seen with administration of tobevibart+elebsiran to date (Asselah 2023b; see also Wedemeyer 2023c) and no significant safety findings have been identified.

[0264] These clinical efficacy data suggest that a combination regimen of tobevibart+elebsiran Q4W has the potential to fulfill an unmet need by providing an efficacious therapy that suppresses HDV viremia (HDV RNA < LLOQ, TND) with monthly dosing that may reduce the likelihood of progression to serious clinical outcomes including hepatic decompensation, cirrhosis, HCC and death.

[0265] Study objectives and endpoints are shown in Table 6.Table 6, Study objectives and associated endpoints.Objectives EndpointsPart 1 (Day 1 through Week 96)To evaluate the antiviral efficacy of HDV RNA < LLOQ, TND at Week 24 tobevibart+elebsiran in participantswith BLV treatment experience114181072933.1To evaluate long-term antiviral HDV RNA < LLOQ, TND at Week 48 efficacy of tobevibart+elebsiran in and Week 96participants with BLV treatmentexperience Change from baseline in HDV RNA at Week 48 and Week 96T o evaluate the effect of Change from baseline in ALT at tobevibart+elebsiran on ALT in Week 24, Week 48, and Week 96 participants with BLV treatmentExperienceTo evaluate the safety of Incidence of TEAEs and SAEs tobevibart+elebsiran through Week 24, Week 48, and Week 96To evaluate the impact of Incidence of decompensated tobevibart+elebsiran on end stage cirrhosis (clinical event or CRT score liver disease outcomes > 7) through Week 48 and Week 96Incidence of HCC or progression to liver failure requiring transplantation or resulting in death through Week 48 and Week 96To evaluate the impact of Change from baseline in liver tobevibart+elebsiran on liver stiffness stiffness as measured by liver in participants with BLV treatment elastography at Week 48 and Week Experience 96T o evaluate the effect of Change from baseline in HBsAg at tobevibart+elebsiran on HBsAg in Week 24, Week 48, and Week 96 participants with BLV treatmentExperience Categorical summary of HBsAg at Week 24, Week 48, and Week 96 Part 2 (Week 96 through Week 240)To evaluate the efficacy of HDV RNA < LLOQ, TND 24 weeks tobevibart+elebsiran in achieving after end of treatment (Week 120) SVR in participants whosystematically interrupt treatmentTo evaluate the efficacy of HDV RNA < LLOQ, TND at Week tobevibart+elebsiran in maintaining 144, Week 192, and Week 240 SVR over time in participants whosystematically interrupt treatment Change from baseline in HDV RNA from tobevibart+elebsiran interruption at Week 96 to Week 120, Week 144, Week 192, and Week 240To evaluate the impact of Change from baseline in ALT from tobevibart+elebsiran interruption on tobevibart+elebsiran interruption at ALT Week 96 to Week 120, Week 144,Week 192, and Week 240115181072933.1T o assess safety after Incidence of AEs, SAEs, and lab tobevibart+elebsiran interruption for abnormalities from time of participants in Arm 1 tobevibart+elebsiran interruption (Week 96) through Week 120, Week 144, Week 192, and Week 240 To evaluate end stage liver disease Incidence of decompensation through outcomes in participants who Week 144, Week 192, and Week 240 systematically interrupt treatment andin participants with chronic HDV who Incidence of HCC or progression to continue treatment liver failure requiring transplantation or resulting in death through Week 144, Week 192, and Week 240 To evaluate liver stiffness after Change from baseline in liver tobevibart+elebsiran interruption in stiffness as measured by liver participants who systematically elastography at Week 144, Week interrupt treatment and in participants 192, and Week 240with chronic HDV who continuetreatmentTo assess the antiviral effect of Categorical summary of HBsAg at tobevibart+elebsiran on serum Week 120, Week 144, Week 192, HBsAg and Week 240To evaluate long-term safety in TEAEs, SAEs through Week 120, participants who continue Week 144, Week 192, and Week 240tobevibart+elebsiran after Week 96Study Design

[0266] This is a Phase 3, prospective, multicenter, randomized, open-label study with 2 parts.

[0267] Part 1 will evaluate the efficacy and safety of tobevibart+elebsiran administered subcutaneously (SC) Q4W compared to continuing BLV therapy for 24 weeks. Participants with chronic HDV infection who are noncirrhotic or have compensated cirrhosis (Child-Pugh-Turcotte [CPT]-A) and have HDV RNA > 500 lU / mL despite receiving BLV 2 mg for > 24 weeks will be randomized 2: 1 to either Arm 1 to receive tobevibart+elebsiran from Day 1 or Arm 2 to continue taking BLV 2 mg QD until Week 24. Randomization will be stratified by screening ALT (ALT < ULN versus ALT > ULN) and cirrhosis status (cirrhotic versus noncirrhotic).Demographic enrollment targets of up to approximately 30% of participants enrolled will have HDV RNA < 2000 lU / mL at screening and up to approximately 30% of participants enrolled will have ALT > ULN at screening. At Week 24, participants who were randomized to Arm 2 will stop taking BLV and begin taking tobevibart+elebsiran 116181072933.1and continue through end of study. All participants will be monitored as detailed in the Schedule of Activities (SoA).

[0268] Part 2 will evaluate the efficacy of tobevibart+elebsiran Q4W in achieving SVR following systematic interruption of tobevibart+elebsiran. Participants in Arm 1 who achieve and maintain HDV RNA < LLOQ, TND between Week 48 and Week 96 will interrupt tobevibart+elebsiran starting at Week 96 (last dose at the Week 92 visit). Participants in Arm 1 who do not achieve HDV RNA < LLOQ, TND by Week 48 or who have confirmed HDV RNA > LLOQ from Week 48 to Week 96 will continue to receive tobevibart+elebsiran as chronic therapy through the end of study. Participants in Arm 2 will continue to receive tobevibart+elebsiran as chronic therapy through end of study. All participants will continue to be monitored through laboratory and clinic evaluations as detailed in the SoA. Participants who meet specified criteria may restart tobevibart+elebsiran.

[0269] The purpose of the study is to (1) evaluate the efficacy and safety of tobevibart+elebsiran administered SC Q4W compared to continuing BLV therapy for 24 weeks, and (2) evaluate the efficacy of tobevibart+elebsiran Q4W in achieving SVR following tobevibart+elebsiran interruption. Safety of tobevibart+elebsiran in participants who are BLV experienced will also be assessed.

[0270] The primary endpoint for Part 1 is undetectable HDV RNA (HDV RNA < LLOQ, TND) at Week 24 in participants receiving tobevibart+elebsiran versus those who continued on 2 mg BLV.

[0271] The primary endpoint for Part 2 of the study is undetectable HDV RNA (HDV RNA < LLOQ, TND) 24 weeks after interruption of tobevibart+elebsiran.Participants will be followed for 3 years following tobevibart+elebsiran interruption to assess durability of SVR.

[0272] Approximately 150 participants will be enrolled into the study globally; enrollment is planned in the countries where BLV has been approved by health authorities and is commercially available for patients living with chronic HDV infection.117181072933.1

[0273] Eligible participants include adult male and nonpregnant, nonlactating females aged > 18 to < 70 years of age with HDV RNA > 500 lU / mL and who have been receiving BLV 2 mg SC QD for at least 24 weeks at Day 1. Participants also must be on NRTI therapy active against HBV for at least 12 weeks prior to Day 1 or have HBV DNA < 20 lU / mL at screening, and currently on locally approved NRTI therapy.

[0274] Intervention groups include: Arm 1 (n=100): tobevibart (300 mg) + elebsiran (200 mg) SC Q4W; to be administered in clinic; and Arm 2 (n=50): BLV (2 mg) SC QD; to be administered at home for 24 weeks followed by tobevibart (300 mg) + elebsiran (200 mg) SC Q4W; to be administered in clinic.

[0275] The total study duration for each participant is planned to be up to 270 weeks. This includes a 6-week screening period, a minimum of 96 weeks study¬ intervention treatment period, followed by either 144 weeks of SVR follow-up or 144 weeks of continued study intervention through Week 240 and a 24-week safety followup period. Participants who discontinue study intervention will be followed for the 24-week safety follow-up. The Sponsor intends to provide a mechanism for eligible participants to continue to access tobevibart+elebsiran, provided development continues, following the end of the study until it becomes locally accessible.

[0276] Participants who are randomized to Arm 1 will receive tobevibart (300 mg) + elebsiran (200 mg) SC Q4W for at least 96 weeks. Participants in Arm 1 who are not eligible for tobevibart+elebsiran interruption will receive up to 240 weeks of tobevibart (300 mg) + elebsiran (200 mg) SC Q4W. Participants who are randomized to Arm 2 will receive BLV 2mg SC QD for 24 weeks, followed by tobevibart (300 mg) + elebsiran (200 mg) Q4W SC for up to an additional 216 weeks.

[0277] Tobevibart is provided as a reconstituted lyophilized powder administered subcutaneously (SC) at 300 mg every 4 weeks. Elebsiran is provided as a liquid administered SC at 200 mg every 4 weeks. Bulevirtide is provided as a reconstituted lyophilized powder administered SC at 2 mg daily.

[0278] The study schema is shown is shown in Figure 6. Table 7 shows the treatment / intervention groups. Figures 7A-7C show the Schedule of Activities for Screening through Week 96 (Arm 1 and Arm 2). Figures 8A-8B show the Schedule of118181072933.1Activities for Week 100 to Week 240 - Systematic Tobevibart+Elebsiran Interruption (Arm 1 only). Figures 9A-9B show the Schedule of Activities for Week 100 to Week 240-Continued Treatment Group (Arm 1 and Arm 2). Figure 10 shows the Schedule of Activities for the Liver Biopsy Substudy (Optional Substudy, Arm 1 only). Figures 11A-11B show the Schedule of Activities of Activities for the Safety Follow-Up Period.Table 7, Treatment groups for clinical study.Arm Intervention Dose Route Number Schedule Group of Doses1 tobevibart+ 300 mg SC Up to 60 Every 4 elebsiran tobevibart weeks 200 mg elebsiran2 BLV 2 mg SC Up to 168 Daily through Week 24 tobevibart+ 300 mg SC 54 Every 4 elebsiran tobevibart weeks from 200 mg elebsiran Week 24 to Week240 SC=subcutaneousParticipant Population

[0279] Participants will include adult male and nonpregnant, nonlactating females aged > 18 to < 70 years with chronic HDV infection, both noncirrhotic and cirrhotic up to METAVIR-F4 / CPT-A, currently on NRTI therapy and BLV 2 mg SC QD. Participants who fulfill the following inclusion and exclusion criteria at screening are eligible for participation in this study.

[0280] Inclusion criteria include the following:1) Adult men and women aged > 18 years (or age of legal consent, whichever is older) to < 70 years at the time of signing informed consent2) HDV RNA > 500 IU / mL at screening3) Receiving BLV 2 mg SC QD for > 24 weeks at Day 1119181072933.14) Noncirrhotic or compensated cirrhotic liver disease at screening.a. Noncirrhotic as defined by liver biopsy with METAVIR F0-F3 or liver stiffness (as measured by elastography, e.g., FibroScan®) < 15 kPa within the 12 months prior to or at screeningb. Compensated cirrhotic as defined by meeting all criteria below: i. Liver biopsy with METAVIR F4 or liver stiffness (as measured by elastography, e.g., FibroScan®) > 15 and < 25 kPa within the 12 months prior to or at screeningii. CPT score of 5 or 6, inclusive at screeningiii. Compensated liver disease based on Investigator assessment The Child-Pugh Turcotte (CPT) Score Assessment of Liver Disease is shown in Table 5.5) Body mass index (BMI) > 18 kg / m2to < 40 kg / m26) On NRTI therapy against HBV for at least 12 weeks prior to Day 1 or have HBV DNA < 20 lU / mL at screening, and currently on locally approved NRTI therapy. Participants must be on one of the following NRTI therapies: tenofovir alafenamide (taken alone or as part of a fixed-dose combination therapy), tenofovir disoproxil fumarate (taken alone or as part of a fixed-dose combination therapy), or entecavir.7) Participants with hepatic impairment with co-morbid diseases requiring medication(s) must be taking the medication(s) without a change in dose for > 3 months prior to screening. All concomitant medications must be approved by the CRO Medical Monitor prior to study enrollment.8) 12-lead ECG within normal limits; or, with no clinically significant abnormalities at screening.

[0281] Exclusion criteria include the following:1) Current or prior history of any of the following:a. Clinically significant laboratory' abnormalities, co-morbid medical condition or planned medical procedure (other than HBV / HDV coinfection) that120181072933.1may interfere with the participant’s treatment, assessment, or compliance with the protocol. Participants under evaluation for a potentially clinically significant illness (other than HBV / HDV coinfection) are also excluded.b. Difficulty with blood collection and / or poor venous access for the purposes of phlebotomy.c. Current or previous (within 24 months of screening) clinically identified hepatic decompensation (e.g., coagulopathy, hyperbilirubinemia, hypoalbuminemia, ascites, encephalopathy, variceal hemorrhage, hepatopulmonary or hepatorenal syndrome) or liver disease requiring paracentesis > 1 time per month or managed with Transjugular Intrahepatic Portosystemic Shunt placement.d. Bone marrow, peripheral blood stem-cell or solid organ transplantation e. Psychiatric hospitalization, suicide attempt, and / or a period of disability as a result of their psychiatric illness within the last 5 years. Participants with psychiatric illness that is well-controlled on a stable treatment regimen for at least 12 months prior to randomization or has not required medication in the last 12 months may be included.f. Malignancy diagnosed or treated within 5 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; ductal carcinoma in situ and cervical carcinoma in situ is allowed if appropriately treated prior to screening); participants under evaluation for malignancy are not eligible.g. Significant drug allergy (such as anaphylaxis or hepatotoxicity) 2) One or more additional known primary or secondary causes of liver disease, other than hepatitis B or hepatitis D (i.e., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, Wilson’s disease, other congenital or metabolic condition affecting the liver, congestive heart failure, etc.).3) History of clinically significant immune complex disease as determined by the Investigator.4) History of anaphylaxis, allergic reactions, hypersensitivity, or intolerance to study drug, its metabolites or excipients121181072933.15) Participants with active HCV (participants with HCV antibodies can be enrolled if screening HCV RNA PCR test is negative).6) Participants with HIV infection (participants with HIV infection can be enrolled if CD4+ T-cell counts are > 500 / mm3and HIV RNA PCR is below the limit of detection for at least 12 months).7) Participants with HAV (participants who are HAV IgM positive can be enrolled if asymptomatic and HAV IgG positive).8) Participants with HEV (participants who are HEV IgM positive can be enrolled if asymptomatic and HEV IgG positive). In cases where acute infection status cannot be determined by serologies a serum or stool HEV RT-PCR can be obtained. The participant is ineligible if PCR is positive.9) Current therapy or therapy within 24 weeks of screening with an immunomodulatory agent (e.g, IFN-a), immune checkpoint inhibitors, immunosuppressants (e.g., disease modifying antirheumatic drugs), cytotoxic or chemotherapeutic agent, or chronic systemic corticosteroids (equivalent of 10 mg prednisone QD).10) Receipt of an investigational HDV antiviral (e.g., lonafamib, antisense oligonucleotide, IFN-lambda) within 24 weeks or 5 half-lives (if known), whichever is longer, of first study intervention administration or are active in the follow-up period of another clinical study involving interventional HDV treatment.11 ) Participants must agree not to take part in any other investigational study at any time during their participation in this study, inclusive of the follow-up period. 12) Receipt of elebsiran or any siRNA targeting HBV or HDV within 24 weeks of first study intervention administration or experienced an ALT flare (ALT > 5 x ULN) while receiving an anti-HBV or -HDV siRNA.13) Receipt of tobevibart or any antibody targeting HBV or HDV within 24 weeks or 5 half-lives (if known), whichever is longer, of first study intervention administration.14) Participants with the following laboratory parameters at screening:122181072933.1a. ALT > 5 x ULNb. Total bilirubin > 2.0 mg / dLc. Serum albumin < 28 g / Ld. Platelet count < 60 x 10^3 / μLe. INR > 1.5f. CrCl < 60 mL / min as estimated using Cockcroft-Gault formula g. WBC Differential, Neutrophils < 1.0 x 10^3 / μL15) History or clinical evidence of alcohol or drug abuse within 6 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). Cannabis use is permitted.

[0282] The following concomitant therapies are not permitted during the study: 1) Participants must abstain from taking prescription drugs outside the care of a prescribing physician and nonprescription drugs (including vitamins, recreational drugs, and dietary or herbal supplements) within 7 days or 5 half-lives (whichever is longer) before the start of study intervention until completion of the follow-up visits, unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the study.2) Use of any of the following systemic medications is prohibited within 24 weeks before study intervention administration and throughout the study: Chronic systemic steroids (prednisone equivalent of > 10 mg / day) or other immunosuppressive agents (Note: corticosteroid administration for the treatment of immune-mediated AEs and short courses of corticosteroids for chronic obstructive pulmonary disease or asthma exacerbations is allowed)3) Additionally, the administration of any potentially hepatotoxic medications during the study should be considered only if no therapeutic alternative can be identified and after a careful consideration of the potential risks and benefits for the participant. Medications that are potentially hepatotoxic or associated with drug-induced liver injury include, but are not limited to, the following (Bjomsson123181072933.12016): Paracetamol (acetaminophen) > 3 g / day, Aspirin > 3 g / day or ibuprofen > 1.2 g / day, Tricyclic antidepressants, Valproate, Phenytoin, Amiodarone, Anabolic steroids. Allopurinol, Amoxicillin-clavulanate, Minocycline, Nitrofurantoin, Sulfamethoxazole / trimethoprim, Erythromycin, Rifampin, Isoniazid, Azole antifungals, Herbal or natural remedies, or concomitant therapies not recommended with coadministration of BLV.References

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[0304] Gupta, S., Elie, S., Arizpe, A., et al. Single-dose pharmacokinetics of VIR-3434, a novel neutralizing monoclonal antibody, in participants with chronic hepatitis B virus infection. (Poster #SAT-177). In: Vir Biotechnology Inc., editor. In: EASL; June 21-24; Vienna, Austria. N / A: The International Liver Congress: European Association for the Study of the Liver 2023.

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[0313] Lampertico, P., Aleman, S., Brunette, M., et al. Efficacy and Safety of 144 Weeks of Bulevirtide 2 mg or 10 mg Monotherapy From the Ongoing Phase 3 Study MYR301. In: Gilead Sciences Inc., editor. In: EASL; June 05-08; Milan, Italy: European Association for the Study of the Liver (EASL) Congress 2024.

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[0331] Zoulim, F., Asselah, T., Chulanov, V., et al. Undetectable HDV RNA Defined as Target Not Detected at the End of Treatment With Bulevirtide and / or Pegylated Interferon Alpha-2a Is an Important Predictor of 48 Weeks Sustained Virologic Response in Chronic Hepatitis Delta. In: Gilead Sciences, I., editor.In: EASL; June 05-08; Milan, Italy: European Association for the Study of the Liver (EASL) Congress 2024a.

[0332] Zoulim, F., Chulanov, V., Lampertico, P., et al. Undetectable HDV RNA at 24 Weeks of Treatment With Bulevirtide and Pegylated Interferon Alfa-2a Combination Therapy Is an Important Predictor of Maintained Response Off-Therapy. In: Gilead Sciences Inc., editor.In: EASL; June 05-08; Milan, Italy: European Association for the Study of the Liver (EASL) Congress 2024b.EXAMPLE 3CLINICAL EVALUATION OF COMBINATION THERAPY VERSUS BULEVIRTIDE TO TREAT CHRONIC HDV INFECTION

[0333] The safety and efficacy of tobevibart and elebsiran combination therapy relative to bulevirtide are evaluated in a Phase 2b, randomized, open-label study clinical study in participants with chronic HDV infection.Summary

[0334] Hepatitis D virus (HDV) is a defective, hepatotropic pathogenic agent dependent on hepatitis B surface antigen (HBsAg) to complete its replication cycle and sustain infection.

[0335] The global prevalence of HDV is estimated to be at least 12 million people. The burden of HDV infection remains high in many African and Asian countries. In Europe and other regions where hepatitis B virus (HBV) vaccination was implemented, HDV prevalence in the native population has been diminishing and shifting to older ages. However, HDV is now re-emerging in these regions largely as a result of immigration from endemic regions. HDV prevalence in the US is estimated to be between 65,000 and 100,000 persons, but HDV infection is acknowledged to be underdiagnosed.131181072933.1

[0336] Chronic HDV infection is the most aggressive form of viral hepatitis due to rapid progression to cirrhosis, liver failure, hepatocellular carcinoma (HCC). and death. Results from a recent meta-analysis examining the association between HDV RNA detectability, liver morbidity and mortality showed that persons with detectable HDV RNA were at higher risk of experiencing liver-related events, including developing cirrhosis. HCC and undergoing liver transplantation, and were at higher risk of mortality compared to those with undetectable HDV RNA. Conversely, the loss of detectable HDV RNA is strongly associated with a lower likelihood to experience liver-related complications, and long-term suppression of HDV RNA is associated with more favorable clinical outcomes. HDV viral suppression is the most indicative surrogate marker for improved long-term clinical outcomes in patients with chronic HDV infection.

[0337] Available treatment options for HDV infection are limited to pegylated-interferon alpha (PEG IFNa) and in some regions of the world, bulevirtide (BLV). PEG IFNa treatment establishes a sustained virologic response in ~25 to 30% of patients after 48 weeks of therapy and a similar percentage of patients achieve this response with treatment longer than 48 weeks, but relapses occur in -50% of patients after longterm follow-up. PEG IFNa is also associated with adverse reactions, the most common of which include flu-like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue and psychiatric sequelae, and is contraindicated in patients with autoimmune diseases, major psychiatric syndromes, and Child-Pugh-Turcotte (CPT)-B or CPT-C stage cirrhosis.

[0338] Bulevirtide, a virus entry inhibitor that targets the sodium taurocholate co-transporting polypeptide (NTCP) receptor, received full approval on 18 July 2023 in the European Union (EU) for treatment of chronic HDV therapy. In the Phase 3 MYR301 study, 12% (6 of 49) of participants achieved undetectable HDV RNA (< lower limit of quantification [LLOQ], target not detected [TND]) at Week 48, which increased to 20% (10 of 49) with 96 weeks of treatment. Therefore, despite continued long-term dosing, approximately 80% of participants will not achieve undetectable HDV RNA.132181072933.1

[0339] Additionally, there are a limited number of investigational agents being studied and developed for the treatment of chronic HDV infection and some may have higher incidence of drug intolerability, frequent dosing, and / or drug drug interactions, further limiting their utility. With HDV viremia being strongly associated with progression to cirrhosis (in patients with or without alanine aminotransferase [ALT] elevations), HCC, liver transplantation and liver-related mortality, there continues to be an unmet need for therapies with improved efficacy to achieve and maintain suppression of viremia (HDV RNA < LLOQ, TND).

[0340] Tobevibart and elebsiran. two investigational agents with mechanisms of action targeting HBsAg at different steps in the HDV replication cycle, are being evaluated. Tobevibart, a monoclonal antibody (mAb) targeting the antigenic loop of HBsAg, prevents viral entry and complexes circulating HBsAg to neutralize virions. Elebsiran is a synthetic, chemically modified small interfering RNA (siRNA) targeting all hepatitis B viral transcripts for degradation, including pregenomic RNA (pgRNA), and is conjugated to a ligand containing 3 N acetyl galactosamine (GalNAc) residues to facilitate delivery to the liver. Preliminary data from the SOLSTICE trial (VIR-CHDV-V201) suggest participants receiving tobevibart 300 mg in combination with elebsiran 200 mg subcutaneously (SC) every 4 weeks achieved and maintained undetectable HDV over time and that participants may achieve HDV RNA < LLOQ, TND off treatment, supporting exploring interruption of treatment with tobevibart+elebsiran.

[0341] Part 1 of this study will evaluate the efficacy and safety of tobevibart+elebsiran combination therapy compared to BLV. The primary efficacy objective is to evaluate the ability of tobevibart+elebsiran combination therapy to achieve HDV RNA < LLOQ, TND by 48 weeks of therapy compared to BLV. The primary safety objective is to evaluate the safety of tobevibart+elebsiran combination therapy and BLV. Part 2 of this study will evaluate the efficacy of tobevibart+elebsiran in generating an HDV sustained virologic response (SVR) by systematically interrupting treatment at Week 96 in participants who achieve and maintain HDV RNA < LLOQ, TND between Week 48 and Week 96. The primary endpoint for Part 2 is133181072933.1HDV RNA < LLOQ, TND at Week 120 (24 weeks after planned tobevibart+elebsiran treatment interruption).Background and Rationale

[0342] HDV, also known as hepatitis delta virus, is a defective, hepatotropic pathogenic agent. The genome is a circular, single-stranded RNA of approximately 1700 nucleotides which only codes for the hepatitis delta antigen. HDV relies on HBsAg to complete its replication cycle, including viral packaging, infectivity, transmission, and inhibition of host immunity. HDV virions can be assembled using HBsAg derived from cccDNA as well as from integrated HBV in hepatocytes (Freitas 2014; Shirvani-Dastgerdi 2015).

[0343] The prevalence of HDV is estimated to be at least 12 million people worldwide (Chen 2019; Miao 2020; Stockdale 2020). A recent literature review undertaken by the Polaris Observatory Collaborators estimated the prevalence of HDV in 25 countries and territories. Estimates ranged widely between countries, from 0.2% in Hong Kong and Mexico to 61.0% in Mongolia, with the overall prevalence among HBsAg positive persons being 2%. The burden of HDV infection remains high in many African and Asian countries. In Europe and other regions where HBV vaccination was implemented, HDV prevalence in the native population has been diminishing and shifting to older ages. However, HDV is now re-emerging in these regions largely as a result of immigration from areas where HDV remains endemic. HDV prevalence in the US is estimated to be between 65,000 and 100,000 persons, but HDV infection is acknowledged to be underdiagnosed (POC 2024; POC 2023; Stockdale 2020). Factors contributing to HDV underdiagnosis include variation in awareness and incomplete testing among people who are HBsAg positive, issues with standardization of confirmatory molecular diagnostic techniques, and a historical lack of effective treatment options even in high-income settings.

[0344] Chronic HDV infection is the most aggressive form of viral hepatitis due to rapid progression to cirrhosis and end stage liver disease including liver failure, HCC and death (Lee 2021; Stockdale 2020). Among persons with chronic HDV infection, 85% to 95% may develop cirrhosis and liver failure within 10 years of134181072933.1infection with approximately 15% developing these complications as early as 1 to 2 years after infection (Kamili 2017; Rizzetto 2015a; WHO 2023). Notably, approximately 50% of HDV infected patients are cirrhotic at diagnosis (Fattovich 1987). HDV viremia has been shown to be a major driver of progression to cirrhosis and / or liver decompensation, and development of HCC (Palom 2020; Romeo 2014). The risk for liver-related events and development of HCC has been found to be 3.8-fold and 2.6-fold higher, respectively, in patients with HDV viremia versus patients without HDV viremia (Kamal 2020). Results from a recent meta-analysis examining the association of HDV RNA detectability and liver morbidity and mortality also showed that patients with detectable HDV RNA were 7 times more likely to undergo liver transplantation and were at higher risk of mortality' compared to those with undetectable HDV RNA (Gish 2024). Conversely, the loss of detectable HDV RNA is strongly associated with a lower likelihood to experience liver-related complications, and longterm suppression of HDV RNA is associated with more favorable clinical outcomes (Wranke 2017; Wranke 2020). HDV viral suppression is the most indicative surrogate marker for improved long-term clinical outcomes in patients with chronic HDV infection. However, available treatment options for HDV infection remain limited.

[0345] For more than 30 years, the only available treatment for HDV infection has been PEG IFNa; it is, however, not approved for this indication (EASL 2017; Sarin 2016; Terrault 2018). PEG IFNa treatment establishes an SVR (clearance of serum HDV RNA after stopping treatment) in around 25 to 30% of patients after 48 weeks of therapy and a similar percentage of patients achieve this response with treatment longer than 48 weeks (Wedemeyer 2011). However, relapses occur in -50% of patients after long-term follow-up (Heidrich 2014). PEG-IFNa is also associated with adverse reactions (e.g, flu-like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue and psychiatric sequelae), which persist as long as patients are on treatment, and is contraindicated in patients with autoimmune diseases, major psychiatric syndromes, and CPT-B or CPT-C stage cirrhosis (Rizzetto 2015b; Sleijfer 2005).135181072933.1

[0346] BLV, a virus entry inhibitor that targets the NTCP receptor, received full marketing authorization on 18 July 2023 in the EU for treatment of chronic HDV infection (EMEA / H / C / 004854 / II / 0019) (EMA 2023). Although 45% of participants receiving 2 mg BLV met the primary endpoint of combined virological (participants with undetectable HDV RNA [< LLOQ with HDV RNA TND] or with HDV RNA decrease by > 2 log 10 lU / ml from baseline) and biochemical response (ALT normalization) at Week 48 in the Phase 3 MYR301 study (NCT03852719 2019), only 12% (6 of 49) of participants achieved undetectable HDV RNA (< LLOQ, TND) at Week 48. and minimally higher response was observed with longer treatment (20% [10 of 49] of participants achieved undetectable HDV RNA at Week 96) (Wedemeyer 2023a; Wedemeyer 2023b). Despite continued long-term dosing, the majority of participants treated with BLV do not achieve undetectable HDV RNA (Wedemeyer 2023a).

[0347] BLV monotherapy or in combination with PEG IFNa is also being investigated as a curative treatment regimen in the MYR301 and MYR204 studies. Interim post-treatment data from the MYR301 study showed that 18% of participants treated with BLV 2 mg and 26% treated with BLV 10 mg for 3 years maintained undetectable HDV RNA (< LLOQ, TND) 24 weeks after stopping BLV (Aleman 2024). Rates of undetectable HDV RNA through Week 48 follow-up were similar compared with Week 24 follow-up for all arms (16% for BLV 2 mg and 24% for BLV 10 mg). Collective data from the BLV studies support evaluating systemic interruption of tobevibart+elebsiran treatment in participants who achieve and maintain undetectable HDV RNA.

[0348] Data from Study MYR204 provided proof of concept that patients with chronic HDV who received 96 weeks of treatment with BLV 2 mg QD or BLV 10 mg QD in combination with PEG IFNa can achieve SVR up to 24 and 48 weeks off therapy (Asselah 2024a). Predictors of SVR 48 weeks included having HDV RNA < LLOQ, TND at the end of treatment with BLV (Week 96) and having HDV RNA < LLOQ, TND at Week 24 on therapy (Zoulim 2024a; Zoulim 2024b). The main driver of participants achieving undetectable HDV RNA in this study is use of PEG-IFNa, as136181072933.1significantly more participants who received the combination of PEG-IFNa and BLV 10 mg achieved HDV RNA < LLOQ, TND at Week 96 on treatment compared to BLV 10 mg alone (70% vs 22%. respectively), with more participants receiving PEG-IFNa and BLV 10 mg achieving SVR after 24 and 48 weeks (46% vs 12%, respectively). As the study has completed, data on longer term sustainability of off treatment response will not be available, therefore it is unknown whether these participants will experience virologic rebound similar to what has been seen in previous PEG-IFNa studies, where approximately 50% of participants relapsed after long-term follow-up (Heidrich 2014).

[0349] Two investigational agents targeting HBsAg at different steps in the HDV replication cycle are being investigated as potential therapeutics to achieve durable suppression of HDV viremia and reduce incidence of end stage liver disease outcomes.

[0350] Tobevibart is an Fc engineered, human IgGlmAb targeting the antigenic loop of HBsAg. Tobevibart acts as an HDV entry inhibitor by blocking interactions between HBsAg on the surface of virions and the cellular receptor(s) on hepatocytes thus preventing viral entry. Tobevibart can also form immune complexes with free and viral associated HBsAg leading to opsonization and elimination of HDV virions from the blood stream. In in vitro experiments, tobevibart completely blocked viral entry and consequently HDV infection in Huh7 NTCP cells.

[0351] Elebsiran is a synthetic, chemically modified siRNA targeting all HBV viral transcripts for degradation and is conjugated to a ligand containing GalNAc residues to facilitate delivery to the liver. By reducing HBsAg production, elebsiran interferes with the production of infectious HDV virions. In in vitro experiments, treatment of HBV / HDV co-infected primary human hepatocytes with elebsiran led to a dose-dependent reduction of secreted infectious HDV virions.

[0352] The Phase 2 SOLSTICE study was designed to evaluate the safety and efficacy of tobevibart and elebsiran as monotherapies and in combination in noncirrhotic and compensated cirrhotic participants with chronic HDV infection on NRTI therapy for suppression of HBV (NCT05461170 2022). In a preliminary analysis, all participants (n=32) who have reached Week 24 in the tobevibart+elebsiran Q4W de137181072933.1novo cohort (Cohort 2C de novo), have achieved a virologic response (HDV RNA < LOD or > 2 log 10 decline from baseline in HDV RNA), with 40.6% (13 of 32) of participants achieving undetectable HDV RNA (HDV RNA < LLOQ, TND); 46.9% (15 of 32) of participants achieving ALT normalization; and 18.8% (6 of 32) of participants achieving undetectable HDV RNA and ALT normalization (Asselah 2024b). ALT flares have not been observed thus far in this cohort; most AEs reported have been transient and mild / moderate in severity and no treatment-related SAEs have been reported.

[0353] Preliminary clinical efficacy data from the SOLSTICE study for treatment of chronic HDV infection suggest tobevibart+elebsiran Q4W therapy is able to suppress and maintain undetectable HDV RNA and has the potential to address the significant unmet need for therapies with improved efficacy, easier administration and the potential to be developed into curative regimens.

[0354] Despite progress in developing therapies for CHD there is still an unmet need. In particular, the majority of patients treated with current therapies do not achieve undetectable HDV or SVR despite long term treatment. Additionally, some patients are unable or unwilling to tolerate the burden of a daily subcutaneous injection or sideeffects from interferon treatment.

[0355] Part 1 of this study will evaluate the efficacy and safety of tobevibart+elebsiran vs BLV as a long-term suppressive regimen. Participants will be patients with CHD with normal or elevated liver biochemical markers who have compensated cirrhosis or are non-cirrhotic and are BLV naive. The primary efficacy endpoint being the proportion of participants achieving virologic suppression (HDV RNA < LLOQ, TND) at Week 48. Safety of tobevibart+elebsiran and BLV will also be assessed.

[0356] Preliminary data from the SOLSTICE study suggest a high proportion of participants receiving tobevibart+elebsiran may achieve the virologic outcomes associated with SVR in the MYR301 and MYR204 studies and supports exploring whether participants can achieve SVR following treatment with tobevibart+elebsiran.138181072933.1

[0357] In Part 2, potential for SVR will be investigated. Participants in Arm 1 who achieve and maintain HDV RNA < LLOQ, TND from Week 48 to Week 96 on treatment will interrupt tobevibart+elebsiran at Week 96 and be followed through Week 240 for SVR. Participants who experience a HDV rebound will restart tobevibart+elebsiran.Benefit Assessment and Objectives

[0358] HDV viremia is strongly associated with progression to cirrhosis (in patients with or without ALT elevations), HCC, liver transplantation and liver-related mortality. Most patients on current therapies do not achieve undetectable HDV RNA. Additionally, there are a limited number of investigational agents being studied and developed for the treatment of chronic HDV infection and some may have higher incidence of drug intolerability, frequent dosing, and / or drug-drug interactions, further limiting their utility. There continues to be an unmet need for therapies with improved efficacy to achieve and maintain suppression of viremia (HDV RNA < LLOQ, TND), leading to improved clinical outcomes.

[0359] HDV is dependent upon HBsAg to form infectious virions, therefore decreasing or eliminating HBsAg expression is expected to inhibit the formation of nascent HDV virions and ultimately reduce HDV viremia. Efficacy data from clinical studies in participants with chronic HBV provide proof of concept of the mechanism of action of tobevibart and elebsiran in reducing HBsAg. When dosed as monotherapy in study VIR 2218 1001, 200 mg elebsiran shows reductions in HBsAg, with deeper declines seen in participants who received 6 doses compared with 2 doses (Lim 2022). Monotherapy with 300 mg tobevibart in study VIR 3434 1002 demonstrates the most durable reductions in HBsAg. All participants in this study achieved > 1 log reduction in HBsAg, and a majority also achieved > 1 log reduction in HBV DNA (Agarwal 2021; Agarw al 2022b). In study VIR 2218 1006, co-administration of elebsiran and tobevibart is associated with a reduction of HBsAg (Gane 2022); the pattern of decline seen in this study is indicative of an additive effect of elebsiran and tobevibart combination therapy.139181072933.1

[0360] Preliminary clinical efficacy data from the SOLSTICE study for treatment of chronic HDV infection demonstrate tobevibart+elebsiran combination therapy is associated with HDV RNA suppression, including achieving undetectable HDV RNA, and ALT normalization in noncirrhotic and compensated cirrhotic participants (Asselah 2024c). Sustained viral suppression (HDV RNA < LLOQ, TND) has also been observed once viral suppression is achieved, with no rebound in HDV RNA observed (Asselah 2024c). ALT flares previously observed with siRNA therapies alone had not been seen with administration of tobevibart+elebsiran to date (Asselah 2023b; see also Wedemeyer 2023c) and no significant safety findings have been identified.

[0361] These clinical data suggest that a combination regimen of tobevibart+elebsiran Q4W, by suppressing viremia (HDV RNA < LLOQ, TND). has the potential to fulfill this unmet need by providing an efficacious therapy with less frequent dosing that may reduce the likelihood of progression to serious clinical outcomes including cirrhosis, hepatic decompensation, HCC, and death.

[0362] Study objectives and endpoints are shown in Table 8.Table 8, Study objectives and associated endpoints.Objectives Endpoints Part 1PrimaryTo evaluate the antiviral efficacy of • HDV RNA < LLOQ, TND at tobevibart+elebsiran vs BLV in Week 48participants with chronic HDVinfectionSecondaryTo evaluate the antiviral efficacy of • HDV RNA < LLOQ at Week 48 tobevibart+elebsiran vs BLV in • Change from baseline in HDV participants with chronic HDV RNA at Week 48infectionTo evaluate the impact of • Change from baseline in ALT attobevibart+elebsiran vs BLV on ALT Week 48140181072933.1Objectives Endpointsin participants with chronic HDVinfectionTo evaluate the long-term antiviral • HDV RNA < LLOQ, TND at efficacy of tobevibart+elebsiran in Week 96participants with chronic HDV • HDV RNA < LLOQ at Week 96 infection (Arm 1) (and maintaining • Change from baseline in HDV SVR overtime in participants who RNA at Week 96 systematically interrupt treatment perprotocol [don’t add continuetreatment population]To evaluate the long-term impact of • Change from baseline in ALT at tobevibart+elebsiran on ALT in Week 96participants with chronic HDVinfection (Arm 1)To evaluate the impact of • Change from baseline ...

Claims

CLAIMSThat which is claimed is:

1. An antibody for use in a method of preventing, eliminating, or reducing the number of or frequency of ALT flares in a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is172181072933.

12. A small interfering RNA molecule (siRNA) for use in a method of preventing, eliminating, or reducing the number of or frequency of ALT flares in a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate. and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is173181072933.

13. A method of preventing, eliminating, or reducing the number of or frequency of ALT flares in a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is4. An antibody for use in a method of treating hepatitis D virus (HDV) infection in a subject having a normal ALT level (less than the upper limit of normal) before treatment, the method comprising administering to the subject:174181072933.1(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is5. A small interfering RNA molecule (siRNA) for use in a method of treating hepatitis D virus (HDV) infection in a subject having a normal ALT level (less than the upper limit of normal) before treatment, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and175181072933.1(b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate. and 2'-fluorouridine-3'-phosphate. respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is6. A method of treating hepatitis D virus (HDV) infection in a subject having a normal ALT level (less than the upper limit of normal) before treatment, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca - 176181072933.13' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g. and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL is7. An antibody for use in a method of treating a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6),177181072933.1wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL iswherein the antibody and siRNA are administered for up to 48 weeks to up to 96 weeks.

8. A small interfering RNA molecule (siRNA) for use in a method of treating a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6),178181072933.1wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate. respectively;Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL iswherein the antibody and siRNA are administered for up to 48 weeks to up to 96 weeks.

9. A method of treating a subject having a hepatitis D virus (HDV) infection, the method comprising administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and (b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO: 5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO: 6), wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively;179181072933.1Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3'-phosphate, 2'-fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'-fluorouridine-3'-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL iswherein the antibody and siRNA are administered for up to 48 weeks to up to 96 weeks.

10. A method of treating a subject having a hepatitis D virus (HDV) infection, the method comprising:(1) administering to the subject:(a) an antibody comprising a light chain amino acid sequence according to SEQ ID NO: 19 and a heavy chain amino acid sequence according to SEQ ID NO: 18; and(b) a small interfering RNA molecule (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'- gsusguGfcAfCfUfucgcuucaca -3' (SEQ ID NO:5) attached to a ligand (L) at the 3' end and the antisense strand comprises 5'- usGfsuga(Agn)gCfGfaaguGfcAfcacsusu -3' (SEQ ID NO:6),wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O- methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O- methyluridine-3'-phosphate, respectively;180181072933.1Af, Cf, Gf, and Uf are 2'-fluoroadenosine-3 '-phosphate, 2'- fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, and 2'- fluorouridine-3 '-phosphate, respectively;(Agn) is adenosine-glycol nucleic acid (GNA);s is a phosphorothioate linkage; andL isand(2) if the subject has detectable HDV RNA, continuing the administration of step 1, and if the subject does not have detectable HDV RNA, discontinuing the administration of step 1.

11. The antibody for use, siRNA for use, or method according to any one of claims 1-10, wherein the light chain CDRL1, CDRL2, and CDRL3 comprise or consist of the amino acid sequences according to KLGNKN (SEQ ID NO: 12), EVK (SEQ ID NO: 13) or VIYEVKYRP (SEQ ID NO: 14), and QTFDSTTVV (SEQ ID NO: 15), respectively.

12. The antibody for use. siRNA for use. or method according to any one of claims 1-11, wherein the heavy chain CDRH1, CDRH2, and CDRH3 comprise or consist of the amino acid sequences according to GRIFRSFY (SEQ ID NO: 8), NQDGSEK (SEQ ID NOV) or INQDGSEK (SEQ ID NO: 10), and AAWSGNSGGMDV (SEQ ID NO: 11), respectively13. The antibody for use, siRNA for use, or method according to any one of claims 1-12, wherein the light chain variable domain (VL) comprises or consists of the amino acid sequence according to SEQ ID NO: 17.181181072933.

114. The antibody for use, siRNA for use, or method according to any one of claims 1-13, wherein the heavy chain variable domain (Vn) comprises or consists of the amino acid sequence according to SEQ ID NO: 16.

15. The antibody for use, siRNA for use, or method according to any one of claims 1-14, wherein the L is conjugated to the siRNA as shown in the following structure:wherein X is O.

16. The antibody for use, siRNA for use, or method according to any one of claims 1-15, wherein the method further comprises preventing, eliminating, or reducing the number of or frequency of ALT flares in the subject, and / or wherein the method results in prevention, elimination, or reduction of the number of or frequency of ALT flares in the subject.

17. The composition for use or method according to any one of claims 1-16, wherein the antibody and siRNA are administered for up to 48 weeks, up to 72 weeks, or up to 96 weeks.

18. The antibody for use, siRNA for use, or method according to any one of claims 1-17, wherein the antibody and siRNA are administered every 4 weeks.

19. The antibody for use, siRNA for use, or method according to any one of claims 1-18, wherein the antibody and siRNA are administered subcutaneously.182181072933.

120. The antibody for use, siRNA for use, or method according to any one of claims 1-19, wherein the antibody is administered at a dose of from 200 mg to 400 mg.

21. The antibody for use, siRNA for use, or method according to claim 20, wherein the antibody is administered at a dose of 300 mg.

22. The antibody for use, siRNA for use, or method according to any one of claims 1-21, wherein the siRNA is administered at a dose of from 100 mg to 300 mg.

23. The antibody for use, siRNA for use, or method according to claim 22, wherein the siRNA is administered at a dose of 200 mg.

24. The antibody for use. siRNA for use. or method according to any one of claims 1-23, wherein the subject has non-cirrhotic or compensated cirrhotic liver disease.183181072933.1

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