daplusiran/tomligisiran (GSK5637608) / J&J, Arrowhead Pharmaceuticals, GSK - LARVOL DELTA

A SECOND-GENERATION HBV SIRNA EXHIBITS BEST-IN-CLASS POTENTIAL IN TREATING CHRONIC HEPATITIS B AND D IN PRECLINICAL STUDIES (AASLD 2026) - "Background: HBV siRNAs such as AB-729, VIR-2218, RG6346 and JNJ-3989 can effectively reduce HBsAg in chronic hepatitis B (CHB) subjects...The potential first/best in class CAM-E, pevifoscorvir sodium (pevy, ALG-000184) and potential best in class HBV ASO ALG-170675 could potentially benefit from the addition of an HBV siRNA in treating CHB and CHD... ALG-127563 demonstrated improved in vitro and in vivo potency when compared with ALG125755 and Ph2/3 siRNAs. Further studies are ongoing."

Preclinical • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation • ASGR

EFFICACY AND SAFETY OF SMALL INTERFERING RNA AGENTS FOR CHRONIC HEPATITIS B: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS (AASLD 2026) - " ResultsEight clinical trials enrolling a total of 1,012 participants evaluating three distinct siRNA agents JNJ-73763989 (JNJ-3989), xalnesiran, or elebsiran were identified. ConclusionsiRNA agents induce profound, clinically meaningful reductions in surface antigen titers. Regimens incorporating JNJ-3989 demonstrate the highest relative probability of short-term response. Co-administration with pegIFN maximizes absolute surface antigen suppression but warrants close monitoring for immunomodulatory ALT flares."

Retrospective data • Review • Hepatitis B • Hepatology • Infectious Disease • Inflammation • TLR7

B-UNITED: A Study of Sequential Therapy With Daplusiran/Tomligisiran (DAP/TOM) Followed by Bepirovirsen in Participants Living With Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2 | N=280 | Not yet recruiting | Sponsor: GlaxoSmithKline

New P2 trial • Hepatitis B • Hepatology • Infectious Disease • Inflammation

B-UNITED: A Study of Sequential Therapy With Daplusiran/Tomligisiran (DAP/TOM) Followed by Bepirovirsen in Participants Living With Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2 | N=264 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatitis B • Infectious Disease • Inflammation

B-UNITED: A Study of Sequential Therapy With Daplusiran/Tomligisiran (DAP/TOM) Followed by Bepirovirsen in Participants Living With Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2 | N=280 | Recruiting | Sponsor: GlaxoSmithKline | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatitis B • Hepatology • Infectious Disease • Inflammation

B-UNITED: A Study of Sequential Therapy With Daplusiran/Tomligisiran (DAP/TOM) Followed by Bepirovirsen in Participants Living With Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2 | N=280 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Oct 2027 ➔ Jul 2027 | Trial primary completion date: Oct 2027 ➔ Jul 2027

Trial completion date • Trial primary completion date • Hepatitis B • Infectious Disease • Inflammation

No impact of low-dose nivolumab addition to JNJ-73763989 on HBsAg declines in chronic hepatitis B: the OCTOPUS-1 study. (PubMed, Clin Gastroenterol Hepatol) - P2 | "JNJ-3989+NA+nivolumab treatment was generally safe and led to robust HBsAg declines; no HBsAg seroclearance was observed."

Journal • Endocrine Disorders • Hepatitis B • Infectious Disease • Inflammation

siRNA JNJ-73763989 decreases HBsAg and HDV RNA in NA-treated hepatitis D patients but may cause ALT flares. (PubMed, J Hepatol) - P2 | "This is the first study showing that the HBsAg-targeting siRNA JNJ-3989 can reduce HDV RNA and HBsAg in patients with CHD. Unexpected ALT elevations were seen in 14 of 21 (67%) participants receiving JNJ-3989 (immediate or deferred)."

Clinical • Journal • Hepatitis B • Infectious Disease • Inflammation

siRNA/Antisense Oligonucleotides (e.g. Vir-2218, Jnj-3989) (APASL 2026) - No abstract available

Hepatitis B

Viral sequence analysis of chronic hepatitis B patients treated with the siRNA JNJ-73763989 in phase II clinical trials. (PubMed, JHEP Rep) - P2 | "This study provides the first comprehensive clinical virology analysis of siRNA-based therapy in HBV infection, offering insights relevant to the broader development of antiviral siRNA therapeutics. The clinical significance of X-trigger substitutions for potential re-treatment with JNJ-3989 or other HBV-targeting siRNAs remains to be determined.ClinicalTrial.gov Identifiers: NCT03982186 and NCT0412954."

Journal • P2 data • Hepatitis B • Infectious Disease • Inflammation

Peginterferon alpha-2a add-on to siRNA JNJ-73763989 in untreated patients with HBeAg-positive chronic hepatitis B virus (HBV) infection: the phase 2 REEF-IT study. (PubMed, Gut) - P2 | "In this population, adding PegIFN-α2a increased HBsAg declines after reductions by JNJ-3989; 20.4% achieved HBsAg seroclearance at least once. Treatment was generally safe with acceptable tolerability."

Journal • P2 data • Hepatitis B • Infectious Disease • Inflammation • IFNA1

Peginterferon-alpha-2a add-on to treatment with siRNA JNJ-73763989 in virologically suppressed chronic hepatitis B: The phase II PENGUIN study. (PubMed, JHEP Rep) - P2 | "However, the addition of PegIFN-α2a to JNJ-3989 ± bersacapavir and NA for the final 12 weeks of a 24-week treatment period did not appear to improve antiviral activity in the studied population. Studies in other CHB groups, including treatment-naïve, HBeAg-positive patients, could help elucidate whether this or other treatment regimens including JNJ-3989 and NA can lead to functional cure in a larger proportion of patients."

Journal • P2 data • Hepatitis B • Infectious Disease • Inflammation • IFNA1

Advances in treatment of hepatitis delta virus infection: Update on novel investigational drugs. (PubMed, World J Virol) - "Significant unmet medical needs remain in the treatment of HDV, and recent advances in drug development offer hope for meaningful advances in drug therapy which may improve virologic response rates and clinical outcomes. This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors (bulevirtide), prenylation inhibitors (lonafarnib), novel IFNs (peginterferon lambda), RNA interference molecules (JNJ-3989, elebsiran), monoclonal antibodies (tobevibart), and nucleic acid polymers (REP2139), and addresses future directions in HDV pharmacotherapy."

Journal • Review • Fibrosis • Gastroenterology • Hepatitis B • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure • Oncology • Solid Tumor

Population Pharmacokinetics of siRNA JNJ-73763989 in Healthy Participants and Patients With Chronic Hepatitis B. (PubMed, Clin Pharmacol Ther) - "The 2:1 dosing ratio of JNJ-73763976 to JNJ-73763924 was predicted to maintain an ~2:1 liver concentration ratio, irrespective of the identified plasma disposition differences between the triggers. Body weight, creatinine clearance, presence of chronic hepatitis B, and hepatic impairment were associated with plasma pharmacokinetic parameters and were included in the final population pharmacokinetic model."

Journal • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • ASGR

REEF-D: A Study of JNJ-73763989 + Nucleos(t)Ide Analog in Participants Co-Infected With Hepatitis B and Hepatitis D Virus (clinicaltrials.gov) - P2 | N=52 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Hepatology • Infectious Disease • Inflammation

SEMI-MECHANISTIC PK/PD MODELING AND SIMULATION OF SEQUENTIAL SIRNA AND BEPIROVIRSEN TREATMENT PREDICTS ADDED BENEFIT IN HBSAG RESPONSE IN SUPPORT OF PHASE 2B DOSE SELECTION (AASLD 2024) - "Funding GSK (218309) Background: Daplusiran/ tomligisiran (DAP/TOM, formerly JNJ-3989) is a fixed combination siRNA that has shown marked declines in HBsAg irrespective of baseline HBsAg but is unlikely to achieve functional cure (FC) alone. The PK-HBsAg model-based simulation results predict an added benefit of sequential DAP/TOM followed by bepirovirsen therapy versus bepirovirsen plus SOC alone due to lowering HBsAg levels with siRNA before starting bepirovirsen treatment. These results support the evaluation of this sequential regimen in a Phase 2b study."

P2b data • PK/PD data • Hepatitis B • Hepatology • Infectious Disease

Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989. (PubMed, Gut) - "Short-duration siRNA treatment suppressed HBsAg expression with a prolonged effect for up to 6 years in some participants."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Study of JNJ 73763989+JNJ 56136379+Nucleos(t)Ide Analog (NA) Regimen Compared to NA Alone in e Antigen Negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2 | N=130 | Completed | Sponsor: Janssen Sciences Ireland UC | Phase classification: P2b ➔ P2

Phase classification • Hepatitis B • Hepatology • Infectious Disease • Inflammation

OCTOPUS-1: An Efficacy and Safety Study of a Combination of JNJ-73763989, Nucleos(t)Ide Analogs (NA), and a Programmed Cell Death Protein Receptor-1 (PD-1) Inhibitor in Chronic Hepatitis B Participants (clinicaltrials.gov) - P2 | N=37 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Hepatology • Infectious Disease • Inflammation

OSPREY: A Study of JNJ-73763989, JNJ-64300535, and Nucleos(t)Ide Analogs in Virologically Suppressed, Hepatitis B e Antigen (HBeAg)- Negative Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Hepatology • Infectious Disease • Inflammation

REEF-1: A Study of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2 | N=471 | Completed | Sponsor: Janssen Sciences Ireland UC | Phase classification: P2b ➔ P2

Phase classification • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A phase 2 open-label study to evaluate safety, tolerability, efficacy, and pharmacodynamics of JNJ-73763989, nucleos(t)ide analogs, and a low-dose PD-1 inhibitor in patients with chronic hepatitis B – Interim results of the OCTOPUS-1 study (EASL-ILC 2024) - "After 24 weeks of treatment with JNJ-3989 + NA + nivolumab the mean decline of HBsAg from baseline was 2 log 10 IU/mL in both arms. Cross-study analysis of JNJ-3989 with VS, HBeAg- patients in REEF-1 did not show an apparent benefit of JNJ-3989 loading dose or nivolumab. Treatment was generally safe and well tolerated but administration of low-dose nivolumab in the study was terminated due to observed TSH suppression."

Clinical • IO biomarker • P2 data • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Downregulation of soluble FASLG as a potential mechanism of enhanced immune-related clearance of infected hepatocytes induced by JNJ-73763989 in HBeAg-negative virologically suppressed chronic hepatitis B patients (EASL-ILC 2024) - "Serum proteomic analyses in VS HBeAg negative patients across two clinical studies showed that JNJ-3989 treatment reduces soluble FASLG and increases serum levels of intracellular hepatocyte proteins, suggestive of increased hepatocyte cell death. As soluble FASLG can interfere with the pro-apoptotic action of cytotoxic T/NK cells through steric hinderance of the membrane bound FAS/FASLG interaction, these data suggest JNJ-3989 treatment might improve clearance of infected hepatocytes by cytotoxic immune cells through restoration of FAS/FASLG mediated apoptotic signaling."

Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • FAS • FASLG • SHMT1 • TNFRSF10B

Long-term hepatitis B surface antigen response after finite treatment with siRNAs ARC-520 or JNJ-3989 (EASL-ILC 2024) - P1/2, P2 | "siRNA treatment suppressed HBsAg expression with a prolonged effect for up to 6 years. The siRNA-100 score consisting of baseline qHBsAg and log reduction at nadir may be indicative of HBsAg level <100 IU/mL at LFU."

Hepatitis B • Hepatology • Infectious Disease • Inflammation

Viral sequence analysis of chronic hepatitis B (CHB) patients treated with the silencing RNA (siRNA) JNJ-3989 in the REEF-1 and REEF-2 clinical studies (EASL-ILC 2024) - P2b | "In JNJ-3989-treated patients who discontinued all treatment and experienced VR, variants within the X-trigger target region were frequently observed during VR but were not selected on-treatment, suggesting that these X-trigger variants developed off-treatment in JNJ-3989 treated patients. Presence of these variants did not impact off-treatment HBsAg kinetics."

Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation