Daplusiran/Tomligisiran + Bepirovirsen for Chronic Hepatitis B
(B-UNITED Trial)
Recruiting in Palo Alto (17 mi)
+76 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
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
Prior Safety Data
Trial Summary
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.
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.
12345Is 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.
678910How 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.
23111213Eligibility 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
I am 18 years old or older.
My HBsAg levels are above 100 IU/mL.
My HBV DNA levels are below 90 IU/mL.
+4 more
Trial 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
Participant Groups
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.
5Treatment groups
Experimental Treatment
Group I: Treatment Arm 2C: Placebo + BepirovirsenExperimental Treatment2 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 + BepirovirsenExperimental Treatment2 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 + BepirovirsenExperimental Treatment2 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 + BepirovirsenExperimental Treatment2 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 + BepirovirsenExperimental Treatment2 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
GSK Investigational SiteSan Francisco, CA
GSK Investigational SiteSan Jose, CA
GSK Investigational SiteMinneapolis, MN
GSK Investigational SiteNew York, NY
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
GlaxoSmithKlineLead Sponsor
References
Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. [2014]Currently available options for the treatment of chronic hepatitis B virus (HBV) infection include standard and pegylated interferon alfa and four oral antiviral agents (lamivudine, adefovir, entecavir, and telbivudine). These treatment strategies are either therapies of finite duration that aim to achieve sustained off-therapy responses, or long-term treatments that aim to maintain on-therapy remission. Pegylated interferon alfa may offer higher sustained off-therapy responses after 1 year, but most patients do not respond. Oral antivirals are the only candidates for long-term treatment of patients with chronic HBV infection. Viral suppression has favourable effects on patients' outcome and modifies the natural history of the disease. Viral resistance is the main drawback of long-term antiviral therapy. Lamivudine monotherapy is associated with higher resistance (year 1, 10-27%; year 2, 37-48%; year 4, 60-65%) than adefovir (year 1, 0%; year 2, 3%; year 5, 29%) or telbivudine (year 1, 3-4%; year 2, 9-22%). Entecavir resistance is rare in naive individuals (year 4,
Chronic hepatitis B: Advances in treatment. [2021]Treatment of chronic hepatitis B (CHB) has markedly improved in the last 15 years due to the availability of direct antivirals which greatly increase therapeutic options. Currently, there are two classes of agents licensed for CHB treatment: standard or pegylated interferon alpha (IFN or Peg-IFN) and five nucleoside/nucleotide analogues (NAs). Long-term treatment with NAs is the treatment option most often used in the majority of CHB patients. Entecavir and tenofovir, the most potent NAs with high barrier to resistance, are recommended as first-line monotherapy by all major treatment guidelines and can lead to long-lasting virological suppression, resulting in histological improvement or reversal of advanced fibrosis and reduction in disease progression and liver-related complications. In this review, we focus on current treatment strategies of chronic hepatitis B and discuss the most recent efficacy and safety data from clinical trials and real life clinical practice. Recent findings of response-guided approaches are also discussed.
New therapies for chronic hepatitis B. [2019]Currently, the only therapy of proven benefit in chronic hepatitis B is interferon-alpha which leads to a long-term benefit in only one-third of patients. New therapies for hepatitis B fall into three categories; antiviral chemotherapy, immunomodulation with cell-based therapies, vaccines or cytokines, and gene therapy such as with antisense oligonucleotides, ribozymes or viral mutants. The most promising immediate approach to therapy is with the new nucleoside antivirals--lamivudine and famciclovir. These drugs are well absorbed orally, result in profound inhibition of circulating hepatitis B virus, and, in some cases, loss of hepatitis B e antigen and improvement in serum aminotransferases. Controlled trials of long-term famciclovir and lamivudine therapy currently underway aim to show whether these drugs are safe and can provide sustained inhibition of viral replication and attentant improvement in liver disease.
[Therapy of chronic hepatitis B]. [2009]Treatment of Chronic Hepatitis B has changed in the last few years with the introduction of oral antivirals (lamivudine, adefovir, entecavir, telbivudine and tenofovir) that together with interferón (standard and pegylated) constitute the therapeutic arsenal. All of these has permitted to increase the therapy indications allowing to treat patients with advance liver disease and decompensate liver disease. The main limitation of oral antivirals is the emergence of HBV strains drug resistance. The challenge are to prevent the emergence of HBV drug resistance and to achieve complete and persistent HBV replication in order to avoid the progression of the liver disease and the development of HBV related complications.
Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies. [2018]To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients.
B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection. [2023]Bepirovirsen (GSK3228836) is an antisense oligonucleotide that induced rapid and prolonged hepatitis B surface antigen (HBsAg) reduction with a favorable safety profile following 4 weeks of treatment in participants with chronic hepatitis B virus (HBV) infection. The objective of the phase 2b study B-Clear is to access the efficacy and safety of bepirovirsen in participants with chronic HBV infection.
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]JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection.
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]JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947).
Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. [2023]Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.
Pharmacokinetics of JNJ-73763989 and JNJ-56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment. [2023]JNJ-73763989 is comprised of 2 short interfering RNAs (siRNAs), JNJ-73763976 and JNJ-73763924, that target hepatitis B virus (HBV) mRNAs for degradation, thereby inhibiting HBV replication. JNJ-56136379 is a capsid assembly modulator that inhibits HBV replication by inducing the formation of empty capsids (CAM-E). In 2 phase 1, open-label, non-randomized, single-center studies, the single-dose pharmacokinetics, safety, and tolerability of JNJ-73763989 or JNJ-56136379 were assessed in participants with moderate hepatic impairment (Child-Pugh Class B) versus participants with normal liver function. Participants in both studies received a single subcutaneous dose of JNJ-73763989 200 mg or oral JNJ-56136379 250 mg, followed by an evaluation of plasma pharmacokinetic parameters and safety assessments. Plasma exposure to JNJ-73763976, JNJ-73763924, and JNJ-56136379 was 1.3- to 1.4-, 1.8- to 2.2-, and 1.1- to 1.3-fold higher in participants with moderate hepatic impairment versus participants with normal liver function; however, these increases were not considered clinically relevant. Both drugs were well tolerated and safe, with 7 (21.9%) participants experiencing 1 or more treatment-emergent adverse events, 3 of which were related to JNJ-56136379. 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.
Oral antivirals for chronic hepatitis B. [2007]Four oral antiviral agents have been approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B: lamivudine, adefovir, entecavir, and telbivudine. This article reviews the durability of response, dose regimen, predictors of response, safety, and problems with resistance of these four agents and of promising agents currently in phase III clinical trials for the treatment of patients who have hepatitis B e antigen-positive and -negative chronic hepatitis B.
Lamivudine treatment of chronic hepatitis B. [2019]Several new nucleoside analogues have been developed which can inhibit hepatitis B replication by at least two logs. Lamivudine is the most widely studied of these new agents. Extensive phase II and III studies in patients with chronic hepatitis B have been completed. The sustained HBeAg seroconversion rate in patients who have received 100 mg lamivudine increases from 17% after a year of treatment to 27% after 2 years of treatment. Histological improvement has been noted in 38%-52% of lamivudine-treated patients, exceeding the improvement seen in placebo recipients. Similar histological improvement has been noted in anti-HBe-positive, DNA- positive patients. Lamivudine can prevent recurrence of hepatitis B after liver transplantation. It is likely that in the absence of immune clearance to accelerate elimination of infected hepatocytes, inhibitors of virus replication such as lamivudine will need to be administered for a long period to reduce the burden of infected hepatocytes in the liver, and to prevent relapse. The drug is generally well tolerated with few direct adverse events. Genotypic mutations have been observed in 23% (range 13-32%). In a study in Asian patients treated for two years the incidence of these mutants increased to 38% (as detected by PCR). Loss of susceptibility to lamivudine has been found to be due to reverse transcriptase amino acid substitutions. Lamivudine is likely to be reserved for patients with replicative hepatitis B infection with active chronic hepatitis, and/or active cirrhosis. Copyright 1998 John Wiley & Sons, Ltd.
New and emerging treatment of chronic hepatitis B. [2018]Conventional treatment of chronic hepatitis B with interferon alfa-2b, lamivudine, and adefovir is limited by low rates of sustained hepatitis B virus DNA suppression and hepatitis B e antigen (HBeAg) seroconversion, increasing rates of drug resistance to the oral agents, and poor tolerability of interferon. Recently several promising new antiviral agents have emerged that possess potent antiviral effects, less toxicity, and have little or no risk of drug resistance. Two new agents, entecavir and peginterferon alfa-2a, have received recent approval by regulatory authorities in the United States and several other countries for the treatment of adults with chronic hepatitis B. In large phase III clinical trials, these agents have demonstrated superior efficacy over lamivudine in both HBeAg-positive and HBeAg-negative patients. Drug resistance occurs at a low rate in lamivudine-refractory patients treated with entecavir or is, to date, nonexistent in nucleoside-naïve patients treated with entecavir and all patients receiving peginterferon. In addition, several novel agents in clinical development, such as emtricitabine, clevudine, telbivudine, valtorcitabine, and tenofovir, have shown promising clinical profiles in patients with chronic hepatitis B. This review summarizes the recent clinical studies of these new agents and discusses the implications of these data for the management of chronic hepatitis B.