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

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

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

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

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

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

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

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

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

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

Intrahepatic changes in immunologic and virologic markers during siRNA JNJ-73763989 (JNJ-3989) based treatment of chronic hepatitis B (CHB) patients: imaging mass cytometry (IMC) analyses from the INSIGHT study (EASL-ILC 2024) - " In INSIGHT, CHB patients who were hepatitis B e-antigen (HBeAg) positive and not currently treated (Group 1) or HBeAg–negative and virologically suppressed by nucleos(t)ide analogs (NA) (Group 2) received 48-weeks of siRNA JNJ-3989 + NA ± CAM-E JNJ-6379. Spatial single-cell profiling of immune and viral markers in the liver from CHB patients demonstrated a decrease in the numbers of infected hepatocytes with a trend towards higher proportions of PDL-1 positive hepatocytes after 40 weeks of treatment with JNJ-3989. Although there was a lower proportion of Ki67-positive cells among the infected hepatocytes, proportions were further reduced in all hepatocytes during treatment, indicating less proliferation."

Clinical • IO biomarker • Hepatitis B • Hepatology • Infectious Disease • Inflammation • B3GAT1 • CD14 • CD20 • CD68 • CD8 • KRT18 • PD-L1 • PTPRC

Robust reduction of HBsAg and HDV RNA levels with low risk for ALT elevations in JNJ-73763989 treated patients with chronic hepatitis D (CHD) and baseline HBsAg levels below 10,000 IU/mL: part 2 of the REEF-D study (EASL-ILC 2024) - "Patients with screening HBsAg <10,000 IU/mL had a low risk for ALT flares and showed a profound and sustained on-treatment suppression of HBsAg and HDV RNA. ALT elevations seen in patients with HBsAg ≥10,000 IU/ml were safely managed with strict stopping criteria for JNJ-3989."

Clinical • Late-breaking abstract • Fibrosis • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure

Efficacy, safety, tolerability, and immunogenicity of JNJ-0535 following a reduction of viral antigen levels through administration of siRNA JNJ-3989 in patients with chronic HBeAg negative hepatitis B - interim data of the OSPREY study (EASL-ILC 2024) - P1 | "Treatment with JNJ-3989, JNJ-0535 and NA, continued or stopped was generally safe and well tolerated. HBsAg lowering, followed by vaccination in OSPREY, showed more favourable HBsAg kinetics during FU in patients that were able to stop NA treatment versus patients who continued NA treatment. A potential role of HBV specific polypositive CD4 T cells needs further elucidation."

Clinical • Late-breaking abstract • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CD4

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

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 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Aug 2026 ➔ Feb 2025

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