bersacapavir (JNJ-56136379) / J&J - LARVOL DELTA

Computational Approaches to Predict Hepatitis B Virus Capsid Protein Mutations That Confer Resistance to Capsid Assembly Modulators. (PubMed, Viruses) - "MM/GBSA correctly predicted the resistance and sensitivity of more than 50% Cp mutations to BAY41-4109 with the structures 5E0I-BC and 5WRE-FA, and to JNJ-56136379 with the 5E0I-FA structure. Our work indicates that only the capsid or CpY132A hexamer structure bound with a CAM with similar chemical scaffold can be used for more accurately predicting the resistance and sensitivity of Cp mutations to a CAM molecule under investigation by molecular docking and/or MM/GBSA methods."

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

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

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

JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analog suppressed patients with chronic hepatitis B: REEF-2. (PubMed, J Hepatol) - P2b | "Finite 48-week treatment with JNJ-3989+JNJ-6379+NA resulted in fewer and less severe posttreatment HBV DNA increases and ALT flares, and a higher proportion of patients with off-treatment HBV DNA suppression, with or without HBsAg suppression, but did not result in FC."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Study of JNJ-73763989, Pegylated Interferon Alpha-2a, Nucleos(t)Ide Analog (NA) With or Without JNJ-56136379 in Treatment-naive Participants With Hepatitis B e Antigen (HBeAg) Positive Chronic Hepatitis B Virus (HBV) Infection (clinicaltrials.gov) - P2 | N=54 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

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

INSIGHT: A Study to Assess Intrahepatic and Peripheral Changes of Immunologic and Virologic Markers in Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2 | N=24 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

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

EFFICACY AND SAFETY OF siRNA JNJ-73763989, CAPSID ASSEMBLY MODULATOR-E (CAM-E) JNJ-56136379, AND NUCLEOS(T)IDE ANALOGS (NA) WITH PEGYLATED INTERFERON ALPHA-2a (PEGIFN-α2a) ADDED IN IMMUNE-TOLERANT PATIENTS WITH CHRONIC HEPATITIS B VIRUS (HBV) INFECTION: INTERIM RESULTS FROM THE PHASE 2 REEF-IT STUDY (AASLD 2023) - P2 | "In these treatment-naïve, HBeAg positive and mainly immune-tolerant patients, adding PegIFN-α2a increased HBsAg declines after levels were reduced by JNJ-3989. 19% of patients achieved transient HBsAg sero-negativity and 15% lost HBeAg."

Clinical • P2 data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

INTRAHEPATIC CHANGES IN VIRAL AND IMMUNE MARKERS FOLLOWING TREATMENT WITH JNJ-73763989 (JNJ-3989) AND NUCLEOS(T)IDE ANALOGS (NAS), IN PATIENTS WITH CHRONIC HEPATITIS B (CHB): INSIGHT WEEK 40 (W40) INTERIM RESULTS (AASLD 2023) - "Background: Treatment of CHB with JNJ-3989 and NA ± JNJ-6379 has shown profound reductions in serum hepatitis B viral (HBV) markers. Treatment of CHB patients with JNJ-3989 resulted in reduction of HBsAg + hepatocytes at week 40 with an increased fraction of non- infected hepatocytes. Changes during treatment were seen in intrahepatic CD8+ T cells (increase of early activated CD8+ T cells in Group1 and depletion of exhausted T cells in Group 2), suggesting that JNJ-3989 + NA treatment combination leads to activation of intrahepatic adaptive immunity."

Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CD8

Binding characteristics of pyrrole-scaffold hepatitis B virus capsid inhibitors and identification of novel potent compounds. (PubMed, RSC Adv) - "This study used in silico computational modeling to provide insights into the binding characteristics between the HBV core protein and two pyrrole-scaffold inhibitors, JNJ-6379 and GLP-26, both in the CAM-Normal (CAM-N) series...Through analyses of the structure-activity and structure-druggability relations of a series of compounds, CU15 emerged as the most promising lead CAM-N compound, exhibiting sub-nanomolar potency and good pharmacokinetic profiles. Overall, the study demonstrated a practical approach to leverage computational methods for understanding key target binding features for rationale-based design, and for guiding the identification of novel compounds."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

INSIGHT: A Study to Assess Intrahepatic and Peripheral Changes of Immunologic and Virologic Markers in Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Jul 2023 ➔ Feb 2023

Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial. (PubMed, Lancet Gastroenterol Hepatol) - P2b | "Although treatment with JNJ-3989 led to a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria, it rarely led to HBsAg seroclearance. However, most patients treated with JNJ-3989 had clinically meaningful reductions in HBsAg that might contribute to a liver environment conducive to better immune control and, in turn, might improve the response to immune-modulating therapies."

Journal • P2b data • Hepatitis B • Hepatology • Immune Modulation • Infectious Disease • Inflammation • Novel Coronavirus Disease • Peptic Ulcer

Viral sequence analysis of chronic hepatitis B patients treated with the capsid assembly modulator JNJ-56136379 in the JADE phase 2a study. (PubMed, Antiviral Res) - P2a | "JNJ-56136379 monotherapy resulted in VBT and was associated with the selection of JNJ-56136379-resistant variants. Efficacy of NA treatment (de novo combination or rescue therapy for VBT) was not impacted, confirming the lack of cross-resistance between these drug classes."

Journal • P2a data • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Association of post-treatment virologic relapse and biochemical flares with HBV serum biomarkers in long-term virologically suppressed HBeAg-negative patients stopping NA treatment: Exploratory analyses from the control arm of the REEF-2 study (EASL-ILC 2023) - P2b | "Background and Aims: REEF-2 (NCT04129554) assessed efficacy and safety of the combination of siRNA JNJ-73763989, CAM-E JNJ-56136379, and nucleos(t)ide analogues (NA) compared to NA only in virologically suppressed hepatitis B e-antigen (HBeAg)-negative patients with chronic hepatitis B (CHB). In patients discontinuing NA treatment, the level of HBV DNA increases during viral relapse correlated with the peak levels of biochemical flares. EOT anti-HBc IgG levels ≥300 IU/mL were strongly associated with the absence of high peak HBV DNA virologic relapse and high peak ALT flares ≥10× ULN, while this association was weaker for EOT HBcrAg and HBsAg levels and absent for HBV RNA."

Biomarker • Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Intrahepatic characterization of virological and immunological markers in two distinct populations of chronic hepatitis B: baseline assessment of core liver and fine needle aspiration biopsies from the investigational INSIGHT study (EASL-ILC 2023) - P2 | "Background and Aims: Treatment of chronic hepatitis B (CHB) patients with the siRNA JNJ- 73763989 (JNJ-3989) and nucleos(t)ide analogs (NAs) ± the CAM-E JNJ-56136379 (JNJ-6379), has shown profound reductions in hepatitis B viral serum markers. The INSIGHT study successfully employed a harmonized approach of multicenter biopsy collection with central sample analysis of liver resident cells at the single cell level. At baseline, NCT HBeAg-positive participants had numerically higher serum viral biomarker levels reflected by greater proportions of HBsAg-, HBcAg-, and HBV RNA-positive hepatocytes than VS HBeAg-negative participants. Interestingly, differences in immune cell RNA expression were modest between groups, with 14 genes significantly differentially expressed in MAIT/CD8+ T-cells or NK cells (associated with False Discovery Rate <10%)."

Biopsy • Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CD8

A Study of JNJ-73763989, Pegylated Interferon Alpha-2a, Nucleos(t)Ide Analog (NA) With or Without JNJ-56136379 in Treatment-naive Participants With Hepatitis B e Antigen (HBeAg) Positive Chronic Hepatitis B Virus (HBV) Infection (clinicaltrials.gov) - P2 | N=54 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Apr 2023 ➔ Sep 2023

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

PENGUIN: A Study of JNJ-73763989, JNJ-56136379, Nucleos(t)Ide Analogs, and Pegylated Interferon Alpha-2a in Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2 | N=48 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

[VIRTUAL] Efficacy and safety results of the phase 2 JNJ-56136379 JADE study in patients with chronic hepatitis B: Interim week 24 data (EASL-ILC-I 2020) - P2a, P2b | "Background and Aims: JNJ-56136379 (JNJ-6379) is a potent capsid assembly modulator producing normal empty capsids (CAM-N). In not treated pts, JNJ-6379+NA increased HBV DNA suppression over NA alone. A mean 0.4 log10 IU/mL HBsAg decline with JNJ-6379 250mg+NA was seen in NT HBeAg+ pts. JNJ- 6379+NA was safe and well tolerated, supporting evaluation of JNJ-6379 in combination with an NA and the siRNA JNJ-73763989 in the ongoing Ph2 REEF-1 study (NCT03982186)."

Clinical • Late-breaking abstract • P2 data • Hepatitis B • Hepatitis C Virus • Hepatology • Infectious Disease

HBcrAg decline in JNJ-56136379-treated chronic hepatitis B patients: Results of a phase 1 study (EASL-ILC 2019) - P1; "Following 28 days of treatment with JNJ-6379, a reduction in HBcrAg levels occurred in a subset of patients, while no changes in HBeAg or HBsAg were observed. This will be examined further in the ongoing Phase 2a JNJ-6379 (JADE) study."

Clinical • P1 data

Sequence analysis of baseline and on-treatment samples from HBV-infected chronic hepatitis B patients treated for 28 days with JNJ-56136379 monotherapy (EASL-ILC 2019) - P1; "Baseline polymorphisms reducing JNJ-6379 in vitro activity were rare. One patient carried a baseline polymorphism which reduced JNJ-6379 activity in vitro and the same aa substitution was emerging in another patient without a clear impact on JNJ-6379 virological response."

Clinical • Monotherapy

Safety, antiviral activity, and pharmacokinetics of a novel hepatitis B virus capsid assembly modulator, JNJ-56136379, in Asian and non-Asian patients with chronic hepatitis B (EASL-ILC 2019) - P1, P2a; "JNJ-6379 was well tolerated, and resulted in similar pharmacokinetics over the entire dose range. Antiviral effects were comparable in Asian and non-Asian CHB patients receiving daily 75 mg doses for 4 weeks. These data support further evaluation of the same dose of JNJ-6379±nucleos (t)ide analogs in a larger cohort of patients at European and Asian sites in a Phase 2a study (NCT03361956).Figure:"

Clinical • PK/PD data

Pharmacokinetics of Jnj-73763989 And Jnj-56136379 (Bersacapavir) In Participants With Moderate Hepatic Impairment. (PubMed, J Clin Pharmacol) - "Overall, the plasma exposures of JNJ-73763989 and JNJ-56136379 were higher in participants with moderate hepatic impairment, but both were well tolerated. Further studies are needed to evaluate the effect of hepatic impairment under multiple dose administration."

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

Randomised phase 2 study (JADE) of the HBV capsid assembly modulator JNJ-56136379 with or without a nucleos(t)ide analogue in patients with chronic hepatitis B infection. (PubMed, Gut) - P2a | "In patients with non-cirrhotic CHB, JNJ-56136379+NA showed pronounced reductions in HBV DNA and HBV RNA, limited HBsAg or HBeAg declines in patients who are NCT HBeAg positive, and was well tolerated, but no clear benefit with regards to efficacy of JNJ-56136379 over NA was observed."

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

PENGUIN: A Study of JNJ-73763989, JNJ-56136379, Nucleos(t)Ide Analogs, and Pegylated Interferon Alpha-2a in Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2 | N=48 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Oct 2022 ➔ May 2022

Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

EFFICACY AND SAFETY OF COMBINATION TREATMENT WITH siRNA JNJ-73763989 AND CAPSID ASSEMBLY MODULATOR JNJ-56136379 (BERSACAPAVIR) IN HBEAG NEGATIVE VIROLOGICALLY SUPPRESSED CHRONIC HEPATITIS B PATIENTS: FOLLOW-UP WEEK 48 END OF STUDY RESULTS FROM REEF-2 (AASLD 2022) - P2b | "Treatment with JNJ-3989 + JNJ-6379 + NA for 48 weeks was generally safe and well tolerated. After stopping all treatments, including NA, at W48, no patient achieved the primary endpoint, but lower HBsAg levels and greater HBV DNA suppression were observed for patients in the active arm after 48 weeks of FU."

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