B-United

18 evidence topics · 4 sources

Objective

Aim stated in the registry record

“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. The study will also include an optional long-term follow-up (LTFU) extension stage for eligible participants.” (opens the source at this quote in a new tab)

Purpose of the sequential regimen stated by the sponsor

“To further expand development of novel sequential regimens, GSK entered an agreement for an exclusive worldwide license to develop and commercialise daplusiran/tomligisiran (GSK5637608, formerly JNJ-3989), an investigational hepatitis B virus-targeted small interfering ribonucleic acid (siRNA) therapeutic.” (opens the source at this quote in a new tab)
“This agreement provides an opportunity to investigate a novel sequential regimen to pursue functional cure in an even broader patient population with bepirovirsen.” (opens the source at this quote in a new tab)

Location and study date

Study dates and status in the registry record

Field	Registry entry
Recruitment status	“Active, not recruiting”
Study start (actual)	“2024-11-11”
Primary completion (estimated)	“2027-05-31”
Study completion (estimated)	“2030-05-17”
First posted	“2024-08-05”
Last update posted	“2026-07-07”

Number of study locations

“This study has 80 locations” (opens the source at this quote in a new tab)

Trial start and status reported by the sponsor

“Phase IIb trials for this sequential therapy started in Q4 2024.” (opens the source at this quote in a new tab)

Study design

Phase 2b, randomized, partially placebo-controlled, double-blind design

“A Phase 2b, Multi-centre, Randomized, Partially Placebo-controlled, Double-blind Study to Investigate the Safety and Efficacy of Sequential Therapy With Daplusiran/Tomligisiran Followed by Bepirovirsen in Participants With Chronic Hepatitis B Virus on Background Nucleos(t)Ide Analogue Therapy (B-United)” (opens the source at this quote in a new tab)

Design details in the registry record

Field	Registry entry
Allocation	“Randomized”
Interventional model	“Sequential Assignment”
Phase	“Phase 2”
Other study identifiers	“218309”
EU trial number	“2024-514507-33-00”

Treatment stages and nucleos(t)ide analogue discontinuation

“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.” (opens the source at this quote in a new tab)

Eligibility criteria

Key inclusion criteria

“Documented chronic HBV infection greater than or equal to (>=) 6 months prior to Screening AND currently receiving stable NA therapy defined as receiving an NA regimen form at least 6 months prior to Screening and with no planned changes to their stable regimen over the duration of the study.” (opens the source at this quote in a new tab)
“Plasma or serum HBsAg concentration greater than (>) 100 international units per milliliter (IU/mL)” (opens the source at this quote in a new tab)
“Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA less than (<) 90 IU/mL” (opens the source at this quote in a new tab)
“Alanine aminotransferase less than or equal to (<=) 2* upper limit of normal (ULN)” (opens the source at this quote in a new tab)
“Participants who are willing and able to cease their NA treatment in accordance with the protocol.” (opens the source at this quote in a new tab)

Key exclusion criteria

“Coinfection with Hepatitis C (cured <12 months at the time of screening), Human immunodeficiency virus or hepatitis D virus” (opens the source at this quote in a new tab)
“History of or suspected liver cirrhosis and/or evidence of cirrhosis.” (opens the source at this quote in a new tab)
“Diagnosed or suspected hepatocellular carcinoma.” (opens the source at this quote in a new tab)
“Prior hepatitis B treatment with bepirovirsen, DAP/TOM, or another oligonucleotide or small interfering RNA (siRNA).” (opens the source at this quote in a new tab)
“Fridericia's QT correction formula (QTcF) >=450 millisecond (msec) (if single electrocardiogram [ECG] at screening shows QTcF >=450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion).” (opens the source at this quote in a new tab)

Treatment

Treatment arms by baseline HBsAg level and DAP/TOM dose

Arm	Registry entry
Arm 1A	“Participants with high Hepatitis B surface antigen (HBsAg) level will receive dose level 1 of DAP/TOM in Treatment Stage 1.”
Arm 1B	“Participants with high HBsAg level will receive dose level 2 of DAP/TOM in Treatment Stage 1.”
Arm 2A	“Participants with low HBsAg level will receive dose level 1 of DAP/TOM in Treatment Stage 1.”
Arm 2B	“Participants with low HBsAg level will receive dose level 2 of DAP/TOM in Treatment Stage 1.”
Arm 2C	“Participants with low HBsAg level will receive Placebo in Treatment Stage 1.”

Bepirovirsen in treatment stage 2

“After Placebo treatment, eligible participants will receive bepirovirsen in Treatment Stage 2.” (opens the source at this quote in a new tab)
“Bepirovirsen will be administered” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using functional cure (HBsAg not detected and HBV DNA below the LLOQ off treatment) as the primary endpoint

Registered primary outcome: functional cure off all HBV treatment

“The functional cure for HBV is defined as sustained suppression (24 weeks or longer) of HBV deoxyribonucleic acid (DNA) <lower limit of quantification (LLOQ) and HBsAg not detected with or without HBsAb after a finite duration of therapy and off all HBV treatment. The number of participants achieving functional cure after discontinuation of all chronic HBV treatments (DAP/TOM, bepirovirsen, and NA treatment) will be reported.” (opens the source at this quote in a new tab)

Registered secondary outcomes: functional cure by baseline HBsAg level and comparison with placebo plus bepirovirsen

“Number of participants achieving functional cure with high Baseline HBsAg level” (opens the source at this quote in a new tab)
“Number of participants achieving functional cure with low Baseline HBsAg level compared against placebo + bepirovirsen arm” (opens the source at this quote in a new tab)
“The number of participants with undetected HBsAg and HBV DNA <LLOQ at the end of bepirovirsen treatment will be reported.” (opens the source at this quote in a new tab)

Functional cure as the recommended endpoint for finite therapies

“The recommended endpoint of novel therapy is functional cure defined as HBsAg loss using a conventional assay for detection of HBsAg (limit of detection 0.05 IU/mL) and HBV DNA below the lower limit of quantification (i.e. < 10 IU/ml) at 24 weeks off-therapy.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Although unproven, lowered HBsAg concentrations could improve the effectiveness of the several immune-modulatory strategies in development, given the preliminary observations observed to date with, for example, immune check point inhibitors.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Response to bepirovirsen alone by baseline HBsAg level

“Response rates declined with increasing baseline HBsAg levels and fell below 10% for genotypes B and C at baseline HBsAg levels exceeding 1,000 IU/mL.” (opens the prescribing information at this quote)

Statistical analysis description

Number of participants (Planned and analyzed)

Enrollment in the registry record

Field	Registry entry
Enrollment (actual)	“283”

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

No evidence found.

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

No evidence found.

Study limitations

Summary: study limitations

B-United is ongoing, with 283 participants enrolled, primary completion estimated for May 2027, and no results posted on ClinicalTrials.gov, so no efficacy or safety data are available for the sequential regimen. Bepirovirsen is given after daplusiran/tomligisiran, an investigational siRNA, so the registered primary outcome describes the combined sequence; the contribution of daplusiran/tomligisiran is assessed only in the low baseline HBsAg stratum, against the placebo plus bepirovirsen arm. The registry does not state the doses of daplusiran/tomligisiran or bepirovirsen, the duration of each treatment stage, or the HBsAg thresholds that define the high and low strata, and inclusion requires HBsAg “greater than (>) 100 international units per milliliter” with no upper limit stated.