Daplusiran/Tomligisiran + Bepirovirsen for Chronic Hepatitis B

(B-UNITED Trial)

Recruiting at 76 trial locations

Overseen By US GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: GlaxoSmithKline

Must be taking: Nucleos(t)ide analogues

Must not be taking: Immunosuppressants, Interferons, Anticoagulants

Disqualifiers: Liver cirrhosis, Hepatitis C, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

280 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you will need to stop taking your current nucleos(t)ide analogue (NA) therapy for chronic hepatitis B as part of the trial.

What data supports the effectiveness of the drug Daplusiran/Tomligisiran + Bepirovirsen for Chronic Hepatitis B?

The research highlights that oral antivirals like lamivudine and famciclovir are effective in reducing hepatitis B virus levels and improving liver function, suggesting that similar antiviral drugs could be beneficial. However, the specific combination of Daplusiran/Tomligisiran + Bepirovirsen is not directly discussed, so its effectiveness may be inferred from the success of other antiviral treatments. ^{1 2 3 4 5}

Is the combination of Daplusiran/Tomligisiran and Bepirovirsen safe for humans?

Bepirovirsen has shown a favorable safety profile in patients with chronic hepatitis B, and JNJ-73763989 (related to Daplusiran/Tomligisiran) was well tolerated in both healthy participants and those with chronic hepatitis B, even in those with moderate liver impairment. ^{6 7 8 9 10}

How is the drug Daplusiran/Tomligisiran + Bepirovirsen unique for treating chronic hepatitis B?

Daplusiran/Tomligisiran + Bepirovirsen is unique because it combines two components that may work together to target the hepatitis B virus in a novel way, potentially offering a new approach compared to existing oral antivirals and interferon treatments, which often face issues like drug resistance and limited long-term effectiveness. ^{2 3 11 12 13}

What is the purpose of this trial?

The study is intended to evaluate the efficacy and safety of 2 different doses of DAP/TOM followed by bepirovirsen in participants living with CHB on standard of care nucleos(t)ide analogue (NA) therapy. The study also aims to identify an optimal dose of DAP/TOM for sequenced therapy with bepirovirsen for further clinical development and to assess the contribution of DAP/TOM to the sequential regimen.

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility Criteria

This trial is for adults over 18 with chronic Hepatitis B who are currently on stable nucleos(t)ide analogue therapy. They must have a specific level of HBsAg and suppressed HBV DNA in their blood, normal liver enzyme levels, and be willing to stop their current treatment as per the study protocol.

Inclusion Criteria

My HBsAg levels are above 100 IU/mL.

My HBV DNA levels are below 90 IU/mL.

My liver enzyme (ALT) levels are within normal range.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Stage 1

Participants receive DAP/TOM or placebo treatment based on their HBsAg level

48 weeks

Regular visits for monitoring and administration

Treatment Stage 2

Eligible participants receive bepirovirsen treatment

48 weeks

Regular visits for monitoring and administration

NA Only Stage

Participants are observed while maintaining background NA treatment

Up to 100 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Treatment Details

Interventions

• Bepirovirsen
• Daplusiran/Tomligisiran

Trial Overview The trial is testing two different doses of Daplusiran/Tomligisiran (DAP/TOM), followed by Bepirovirsen, to see how effective and safe they are for treating chronic Hepatitis B. It also seeks the best dose of DAP/TOM to use before Bepirovirsen in future treatments.

Participant Groups

Group I: Treatment Arm 2C: Placebo + Bepirovirsen Experimental Treatment 2 Interventions

Participants with low HBsAg level will receive Placebo in Treatment Stage 1. After Placebo treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.

Group II: Treatment Arm 2B: DAP/TOM + Bepirovirsen Experimental Treatment 2 Interventions

Participants with low HBsAg level will receive dose level 2 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.

Group III: Treatment Arm 2A: DAP/TOM + Bepirovirsen Experimental Treatment 2 Interventions

Participants with low HBsAg level will receive dose level 1 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.

Group IV: Treatment Arm 1B: DAP/TOM + Bepirovirsen Experimental Treatment 2 Interventions

Participants with high HBsAg level will receive dose level 2 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.

Group V: Treatment Arm 1A: DAP/TOM + Bepirovirsen Experimental Treatment 2 Interventions

Participants with high Hepatitis B surface antigen (HBsAg) level will receive dose level 1 of DAP/TOM in Treatment Stage 1. After DAP/TOM Treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Findings from Research

Pegylated interferon alfa can lead to higher sustained off-therapy responses for chronic hepatitis B virus (HBV) infection, but most patients do not respond, making it less effective for long-term treatment.

Oral antiviral agents like entecavir show low resistance rates and are preferred for long-term therapy, although lamivudine has a significantly higher risk of developing resistance over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. Papatheodoridis, GV., Manolakopoulos, S., Dusheiko, G., et al.[2014]

Direct antivirals have significantly improved the treatment of chronic hepatitis B (CHB) over the past 15 years, with nucleoside/nucleotide analogues (NAs) like entecavir and tenofovir being the most effective options for long-term therapy.

These first-line treatments not only achieve long-lasting virological suppression but also lead to improvements in liver health, including reversal of advanced fibrosis and reduced risk of liver-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic hepatitis B: Advances in treatment. Santantonio, TA., Fasano, M.[2021]

Interferon-alpha is currently the only proven therapy for chronic hepatitis B, but it only benefits about one-third of patients, highlighting the need for more effective treatments.

New nucleoside antivirals like lamivudine and famciclovir show promise as they significantly inhibit the hepatitis B virus and may lead to improvements in liver health, with ongoing trials assessing their long-term safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapies for chronic hepatitis B. Hoofnagle, JH., Lau, D.[2019]

The introduction of oral antivirals for Chronic Hepatitis B treatment has expanded therapy options, allowing for the treatment of patients with advanced and decompensated liver disease.

A major challenge remains the emergence of drug-resistant HBV strains, highlighting the need for strategies to prevent resistance and achieve sustained viral suppression to prevent liver disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapy of chronic hepatitis B]. Buti, M., Esteban, R.[2009]

In a study of 50 chronic hepatitis B patients resistant to entecavir, those treated with a combination of adefovir and entecavir showed significantly higher virologic response rates compared to those treated with adefovir and lamivudine, with cumulative response rates reaching 76% at 36 months.

Patients with lower baseline HBV DNA levels and an initial virologic response after 3 months had the best outcomes, achieving up to 90% virologic response rates, suggesting that these factors are important for predicting treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies. Kim, HS., Yim, HJ., Jang, MK., et al.[2018]

Bepirovirsen, an antisense oligonucleotide, showed promising results in reducing hepatitis B surface antigen (HBsAg) levels with a favorable safety profile after just 4 weeks of treatment in patients with chronic hepatitis B virus (HBV) infection.

The phase 2b B-Clear study enrolled 457 participants and aims to evaluate the long-term efficacy of bepirovirsen in achieving HBsAg and HBV DNA seroclearance after treatment, comparing results in patients receiving nucleos(t)ide analog therapy versus those not on therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection. Cremer, J., Elston, R., Campbell, FM., et al.[2023]

In a study involving 57 treatment-naïve patients with chronic hepatitis B virus (HBV) infection, JNJ-6379 was well tolerated, with no serious adverse events reported, indicating a favorable safety profile for this antiviral treatment.

JNJ-6379 demonstrated significant antiviral activity, with 32% of patients achieving undetectable levels of HBV DNA after 4 weeks of treatment, suggesting its effectiveness in reducing viral load in chronic HBV patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection. Zoulim, F., Lenz, O., Vandenbossche, JJ., et al.[2021]

In two phase 1 studies involving healthy participants and chronic hepatitis B patients, JNJ-73763989 was found to be generally safe and well tolerated, with all adverse events reported as mild to moderate.

The pharmacokinetics of JNJ-73763976 and JNJ-73763924 showed a dose-proportional increase in plasma concentrations, with a short half-life of 4-9 hours, and no significant differences in pharmacokinetics between Japanese and non-Japanese participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B. Gane, E., Yuen, MF., Kakuda, TN., et al.[2022]

In a phase 2b trial involving 457 participants with chronic hepatitis B virus (HBV) infection, bepirovirsen treatment led to sustained loss of hepatitis B surface antigen (HBsAg) and HBV DNA in 9-10% of participants, indicating its potential efficacy as a treatment.

While bepirovirsen showed some effectiveness, it was associated with more adverse events, such as injection-site reactions and fatigue, compared to placebo, highlighting the need for further studies to evaluate its safety and long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. Yuen, MF., Lim, SG., Plesniak, R., et al.[2023]

In two phase 1 studies involving participants with moderate hepatic impairment and normal liver function, the siRNA treatment JNJ-73763989 and the capsid assembly modulator JNJ-56136379 were found to be safe and well tolerated, with only 21.9% of participants experiencing treatment-emergent adverse events.

Plasma exposure to the drugs was higher in participants with moderate hepatic impairment, but these increases were not clinically significant, suggesting that the treatments can be safely administered even in individuals with liver issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of JNJ-73763989 and JNJ-56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment. Kakuda, TN., Halabi, A., Klein, G., et al.[2023]

The FDA has approved four oral antiviral agents—lamivudine, adefovir, entecavir, and telbivudine—for treating chronic hepatitis B, each with varying durability of response and safety profiles.

The review also highlights ongoing phase III clinical trials for new agents, indicating continued advancements in treatment options for both hepatitis B e antigen-positive and -negative patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral antivirals for chronic hepatitis B. Min, AD., Dienstag, JL.[2007]

Lamivudine, a nucleoside analogue, has shown significant efficacy in treating chronic hepatitis B, with sustained HBeAg seroconversion rates increasing from 17% after one year to 27% after two years, and histological improvement observed in 38%-52% of treated patients compared to placebo.

The drug is generally well tolerated with few adverse events, but 23% of patients developed genotypic mutations leading to reduced susceptibility, which increased to 38% in Asian patients after two years, indicating the need for long-term treatment and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lamivudine treatment of chronic hepatitis B. Dusheiko, G.[2019]

New antiviral agents like entecavir and peginterferon alfa-2a have been approved for treating chronic hepatitis B and show superior efficacy compared to lamivudine in large phase III trials involving HBeAg-positive and HBeAg-negative patients.

These new treatments have low rates of drug resistance, making them safer options for patients, especially those who are resistant to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New and emerging treatment of chronic hepatitis B. Keeffe, EB., Marcellin, P.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. [2014]

2. United States pubmed.ncbi.nlm.nih.gov

Chronic hepatitis B: Advances in treatment. [2021]

3. England pubmed.ncbi.nlm.nih.gov

New therapies for chronic hepatitis B. [2019]

4. Argentina pubmed.ncbi.nlm.nih.gov

[Therapy of chronic hepatitis B]. [2009]

5. United States pubmed.ncbi.nlm.nih.gov

Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection. [2021]

8. England pubmed.ncbi.nlm.nih.gov

JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of JNJ-73763989 and JNJ-56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Oral antivirals for chronic hepatitis B. [2007]

12. England pubmed.ncbi.nlm.nih.gov

Lamivudine treatment of chronic hepatitis B. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

New and emerging treatment of chronic hepatitis B. [2018]