Section 4 of 6
Clinical evidence
684 evidence topics · 69 sources
Study summaries
B-Well 1
Objective
Purpose stated in the ClinicalTrials.gov brief summary
Main objective in the EU Clinical Trials Information System record
Main and secondary objectives in the EU Clinical Trials Register record
Aims of both B-Well trials stated by the company
Location and study date
Study dates and status in the ClinicalTrials.gov record
“Study Start (Actual) 2022-12-07” (opens the source at this quote in a new tab)
“Primary Completion (Actual) 2025-11-11” (opens the source at this quote in a new tab)
“Study Completion (Actual) 2026-04-15” (opens the source at this quote in a new tab)
“First Posted 2022-11-30” (opens the source at this quote in a new tab)
“Last Update Posted 2026-07-08” (opens the source at this quote in a new tab)
“Completed” (opens the source at this quote in a new tab)
“No Results Posted” (opens the source at this quote in a new tab)
Number of locations in the ClinicalTrials.gov record
Study locations by country in the ClinicalTrials.gov record
EU and EEA member states, trial start, and end of trial in the EU Clinical Trials Information System record
Planned sites in the European Economic Area and regulatory and ethics decisions in the EU Clinical Trials Register record
Regions with planned trial sites in the EU Clinical Trials Register record
Countries in both B-Well trials stated by the company
Trial start in the company pipeline appendix
Initiation of the two phase 3 studies announced by the licensor
Study design
Official title in the ClinicalTrials.gov record
Design details in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Phase | “Phase 3” |
| Primary purpose | “Treatment” |
| Allocation | “Randomized” |
| Interventional model | “Parallel Assignment” |
| Model description | “This is a multicenter, randomized, double-blind, placebo-controlled study.” |
| Masking | “Quadruple” |
| Masking description | “This will be a double blinded study in which investigators/site staff and the Sponsor will remain blinded to treatment assignment.” |
Four study stages, stratification, and total duration in the ClinicalTrials.gov record
Two identically designed phase 3 trials in the prescribing information
Nucleos(t)ide analogue cessation at week 48 and cessation eligibility criteria
Criteria to restart nucleos(t)ide analogue therapy after cessation
Replicate double-blind design in the primary publication
“In two replicate, double-blind trials (B-Well 1 and B-Well 2), we randomly assigned adults with noncirrhotic chronic HBV infection in a 2:1 ratio to receive subcutaneous bepirovirsen (at a weekly dose of 300 mg) or placebo for 24 weeks.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“Eligible patients discontinued NA therapy at 48 weeks.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
Placebo control, treatment arms, and data monitoring committee in the EU Clinical Trials Register record
“Therapeutic confirmatory (Phase III) Yes” (opens the source at this quote in a new tab)
“Placebo Yes” (opens the source at this quote in a new tab)
“Number of treatment arms in the trial 2” (opens the source at this quote in a new tab)
“Trial has a data monitoring committee Yes” (opens the source at this quote in a new tab)
Design of both B-Well trials stated by the company
Eligibility criteria
Key inclusion and exclusion criteria summarized in the prescribing information
Population described in the primary publication
Inclusion criteria in the ClinicalTrials.gov record
Exclusion criteria: coinfection, cirrhosis, malignancy, vasculitis, and extrahepatic disorders in the ClinicalTrials.gov record
Exclusion criteria: prior and concomitant therapy in the ClinicalTrials.gov record
Definition of cirrhosis for exclusion in the EU Clinical Trials Register record
Other exclusion criteria in the EU Clinical Trials Register record
Treatment
Hibsago or placebo dosing regimen with background nucleos(t)ide analogue therapy
Arms and interventions in the ClinicalTrials.gov record
| Arm | Registry value |
|---|---|
| Experimental arm | “Experimental: Bepirovirsen”; “Bepirovirsen will be administered.” |
| Placebo arm | “Placebo Comparator: Placebo”; “Matching placebo will be administered.” |
Treatment arms in the company pipeline appendix
Investigational product and placebo in the EU Clinical Trials Register record
| Field | Registry value |
|---|---|
| Pharmaceutical form | “Solution for injection” |
| Route of administration | “Subcutaneous use” |
| Concentration unit | “mg/ml milligram(s)/millilitre” |
| Concentration number | “Concentration number 150” |
| Current sponsor code | “GSK3228836” |
| Placebo used | “Is a Placebo used in this Trial? Yes” |
| Pharmaceutical form of the placebo | “Pharmaceutical form of the placebo Solution for injection” |
| Route of administration of the placebo | “Route of administration of the placebo Subcutaneous use” |
| Care after the trial | “To continue with standard of care.” |
Study outcomes
Rationale for using functional cure as the primary endpoint
Registered primary outcome measure in the ClinicalTrials.gov record
Registered secondary outcome measures in the ClinicalTrials.gov record
Primary and secondary end points and time point in the EU Clinical Trials Register record
Primary and three key secondary endpoints assessed at week 72 in the prescribing information
Functional cure definition and assay thresholds in the company release
Functional cure definition and primary outcome in the primary publication
“Treatment with bepirovirsen, an antisense oligonucleotide targeting hepatitis B virus (HBV) transcripts, has the potential to result in a functional cure, defined by at least 24 weeks of a sustained HBV DNA level below the lower limit of quantification (LLOQ) and hepatitis B surface antigen (HBsAg) loss after fixed-duration therapy.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“The primary outcome was a functional cure at week 72.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
Functional cure as the preferred primary endpoint: AASLD-EASL treatment endpoints conference
“Of all these surrogate endpoints, HBsAg loss is considered to be the most relevant because HBsAg seroclearance is associated with sustained off-treatment improvement in clinical outcomes.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Moreover, HBsAg seroclearance is easy to measure with standardized and widely available assays.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“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
Clinical endpoints are unfeasible as trial endpoints: AASLD-EASL treatment endpoints conference
“These clinical endpoints however typically develop over decades and are therefore unfeasible to be used as primary therapeutic endpoints for clinical trials of new investigational agents.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Although long-term sustained off-treatment HBV DNA suppression is associated with similar improvements in clinical outcomes as HBsAg loss, in patients with cirrhosis, it is not reliably durable, and there is a 15-40% lifetime chance of disease reactivation.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Nucleos(t)ide analogue withdrawal in trial control arms: AASLD-EASL treatment endpoints conference
“If off-treatment response is a primary endpoint, then NA should be withdrawn from both active treatment and control arms but only if stringent predetermined criteria based on HBsAg levels and other parameters are met to ensure safety.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Efficacy endpoints and add-on placebo-controlled design for finite therapy: FDA guidance
Functional cure as the primary endpoint of phase II/III trials: EASL clinical practice guideline
Functional cure as the optimal endpoint for new therapies: bepirovirsen phase 2b design report
“Recently, functional cure, defined as durable hepatitis B surface antigen (HBsAg) loss with or without HBsAg seroconversion and undetectable HBV DNA, has been accepted as the optimal endpoint for new HBV therapies” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Functional cure is rare (≤ 5%) with NA therapy” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Statistical analysis description
Number of participants (Planned and analyzed)
Planned number of participants in the EU Clinical Trials Register record
“In the EEA 191” (opens the source at this quote in a new tab)
“In the whole clinical trial 900” (opens the source at this quote in a new tab)
“Number of subjects for this age range: 738” (opens the source at this quote in a new tab)
“Number of subjects for this age range: 162” (opens the source at this quote in a new tab)
Actual enrollment in the ClinicalTrials.gov record
Randomized participants and full analysis set in the prescribing information
Participants analyzed for the primary endpoint in the primary publication
Pooled B-Well 1 and B-Well 2 results: participants in both trials
Pooled B-Well 1 and B-Well 2 results: participants in the pooled safety population
Description of analysis sets
Full analysis set used for efficacy
Statistical methods for the primary endpoint: stratified common rate difference and exact Cochran-Mantel-Haenszel test
Statistical methods for the key secondary endpoints in participants with baseline HBsAg up to 1,000 IU/mL
Ranked order of the primary and key secondary endpoints
Pooled B-Well 1 and B-Well 2 results: pooled safety data set, weeks 1 to 36
Pooled B-Well 1 and B-Well 2 results: subgroup analyses of the pooled population
Pooled B-Well 1 and B-Well 2 results: post hoc analysis of predictors of nonresponse
Pooled B-Well 1 and B-Well 2 results: durability population of participants who stopped nucleos(t)ide analogue therapy
Results
Participant disposition
Randomized participants and full analysis set
Pooled B-Well 1 and B-Well 2 results: participants who received at least one dose
Pooled B-Well 1 and B-Well 2 results: participants who stopped NrtI therapy at week 48
Baseline characteristics
Pooled B-Well 1 and B-Well 2 results: participants aged 65 years and older
Efficacy results
Primary and key secondary endpoints met
Primary endpoint: sustained HBV DNA suppression and HBsAg not detected 24 weeks after NrtI cessation, baseline HBsAg up to 3,000 IU/mL
| Measure (full analysis set) | Value |
|---|---|
| Hibsago, n/N (%) | “127/650 (20)” |
| Placebo, n/N (%) | “0/328 (0)” |
| Common rate difference, % (95% CI) | “17 (14.6, 20.3)” |
| p-value | “<0.0001” |
“The percentage of patients with a functional cure at week 72 was significantly higher with bepirovirsen than with placebo both in the B-Well 1 trial (in 127 of 650 patients [20%] vs. none of 328 patients)” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
Key secondary endpoint: sustained HBV DNA suppression and HBsAg not detected, baseline HBsAg up to 1,000 IU/mL
| Measure (full analysis set) | Value |
|---|---|
| Hibsago, n/N (%) | “105/426 (25)” |
| Placebo, n/N (%) | “0/214 (0)” |
| Rate difference, % (95% CI) | “25 (20.8, 29.0)” |
| p-value | “<0.0001” |
Key secondary endpoints: sustained HBV DNA suppression below the LLOQ 24 weeks after NrtI cessation
| Measure (full analysis set) | Value |
|---|---|
| Baseline HBsAg up to 3,000 IU/mL: Hibsago, n/N (%) | “151/650 (23)” |
| Baseline HBsAg up to 3,000 IU/mL: placebo, n/N (%) | “0/328 (0)” |
| Baseline HBsAg up to 3,000 IU/mL: common rate difference, % (95% CI) | “21 (17.9, 24.0)” |
| Baseline HBsAg up to 1,000 IU/mL: Hibsago, n/N (%) | “124/426 (29)” |
| Baseline HBsAg up to 1,000 IU/mL: placebo, n/N (%) | “0/214 (0)” |
| Baseline HBsAg up to 1,000 IU/mL: rate difference, % (95% CI) | “29 (25.0, 33.6)” |
| p-value, each stratum | “<0.0001” |
Functional cure at week 72 by baseline HBsAg stratum, pooled and B-Well 1
| Population | Value |
|---|---|
| Pooled, baseline HBsAg up to 3,000 IU/mL: rate | “19% vs. 0% (placebo)” |
| Pooled, baseline HBsAg up to 3,000 IU/mL: participants | “233 of 1,220 vs. 0 of 614” |
| B-Well 1, baseline HBsAg up to 3,000 IU/mL: rate | “B-Well 1: 20% vs. 0%” |
| B-Well 1, baseline HBsAg up to 3,000 IU/mL: participants | “127 of 650 vs. 0 of 328” |
| Pooled, baseline HBsAg up to 1,000 IU/mL: rate | “26% vs. 0% (placebo)” |
| Pooled, baseline HBsAg up to 1,000 IU/mL: participants | “200 of 768 vs. 0 of 393” |
| B-Well 1, baseline HBsAg up to 1,000 IU/mL: rate | “B-Well 1: 25% vs. 0%” |
| B-Well 1, baseline HBsAg up to 1,000 IU/mL: participants | “105 of 426 vs. 0 of 214” |
Pooled B-Well 1 and B-Well 2 results: sustained HBV DNA suppression below the LLOQ
Pooled B-Well 1 and B-Well 2 results: HBsAg at or below 100 IU/mL, exploratory analysis
Pooled B-Well 1 and B-Well 2 results: subgroups with lower response
Pooled B-Well 1 and B-Well 2 results: response by HBV genotype
Pooled B-Well 1 and B-Well 2 results: HBsAg below 1 IU/mL at treatment week 12 as a predictor of response, post hoc analysis
Pooled B-Well 1 and B-Well 2 results: durability of response at weeks 72 and 96 after NrtI cessation
Pooled B-Well 1 and B-Well 2 results: NrtI restart through week 96
Nucleotide polymorphisms in the bepirovirsen binding site
| Population and measure | Value |
|---|---|
| Baseline HBsAg up to 3,000 IU/mL: baseline polymorphisms, % (n/N) | “6 (7/123)” |
| Baseline HBsAg up to 3,000 IU/mL: treatment-emergent mutations, % (n/N) | “5 (2/42)” |
| Baseline HBsAg up to 1,000 IU/mL: baseline polymorphisms, % (n/N) | “3 (2/69)” |
| Baseline HBsAg up to 1,000 IU/mL: treatment-emergent mutations, % (n/N) | “5 (1/22)” |
Health-related quality of life and patient-reported outcomes
No evidence found.
Safety results
Pooled B-Well 1 and B-Well 2 results: overall, serious, and grade 3 or higher adverse events
“In a pooled analysis at 72 weeks, adverse events were reported in 91% of the patients in the bepirovirsen groups and in 73% of those in the placebo groups; serious adverse events were reported in 7% and 4% of the patients, respectively.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“During the treatment period, adverse events of grade 3 or higher were reported in 16% of the patients who received bepirovirsen and in 3% of those who received placebo; increases in the alanine aminotransferase level were the most common grade 3 adverse events with bepirovirsen (in 6% of the patients).” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
Pooled B-Well 1 and B-Well 2 results: discontinuation due to adverse events
Pooled B-Well 1 and B-Well 2 results: adverse reactions in at least 3% of Hibsago recipients, weeks 1 to 36
Pooled B-Well 1 and B-Well 2 results: injection site reactions, weeks 1 to 36
Pooled B-Well 1 and B-Well 2 results: selected laboratory abnormalities worsened from baseline, weeks 1 to 36
| Laboratory category | Hibsago (N = 1,223) | Placebo (N = 611) |
|---|---|---|
| ALT 3 to less than 5 times ULN | “10%” | “<1%” |
| ALT 5 to less than 10 times ULN | “8%” | “0” |
| ALT 10 to less than 20 times ULN | “4%” | “0” |
| ALT 20 times ULN or higher | “2%” | “<1%” |
| AST 3 to less than 5 times ULN | “6%” | “<1%” |
| AST 5 to less than 10 times ULN | “4%” | “<1%” |
| AST 10 to less than 20 times ULN | “1%” | “<1%” |
| AST 20 times ULN or higher | “<1%” | “0” |
| Total bilirubin ULN to less than 1.5 times ULN | “8%” | “11%” |
| Total bilirubin 1.5 to less than 2 times ULN | “2%” | “2%” |
| Total bilirubin 2 times ULN or higher | “<1%” | “<1%” |
| Platelets 100 to less than 140 x 10^9/L | “37%” | “7%” |
| Platelets 75 to less than 100 x 10^9/L | “8%” | “<1%” |
| Platelets 50 to less than 75 x 10^9/L | “2%” | “<1%” |
| Platelets 25 to less than 50 x 10^9/L | “<1%” | “0” |
| Platelets less than 25 x 10^9/L | “<1%” | “0” |
| ANC 500 to less than 1,000 cells/mm3 | “8%” | “3%” |
| ANC 100 to less than 500 cells/mm3 | “1%” | “<1%” |
| eGFR decline of 15% to less than 30% from baseline | “51%” | “30%” |
| eGFR decline of 30% to less than 50% from baseline | “17%” | “6%” |
| eGFR decline of 50% or more from baseline | “1%” | “<1%” |
| uACR 0.3 mg/mg or higher | “2%” | “1%” |
Pooled B-Well 1 and B-Well 2 results: ALT increases leading to treatment pause or discontinuation
Pooled B-Well 1 and B-Well 2 results: thrombocytopenia and platelet count decline
Pooled B-Well 1 and B-Well 2 results: neutrophil count decline
Pooled B-Well 1 and B-Well 2 results: eGFR decline
Pooled B-Well 1 and B-Well 2 results: cutaneous vasculitis
Less common adverse reactions: hypersensitivity and angioedema
Pooled B-Well 1 and B-Well 2 results: anti-drug antibodies
Most frequently observed adverse events
Study limitations
Summary: study limitations
B-Well 1 administered bepirovirsen for 24 weeks and assessed the primary endpoint at week 72, 24 weeks after possible cessation of NrtI therapy; the longest reported follow-up is week 96, and it covers the 295 of 1,220 pooled bepirovirsen recipients who stopped NrtI therapy at week 48. Eligibility required stable NrtI therapy, HBsAg above 100 and up to 3,000 IU/mL, HBV DNA below 90 IU/mL, and ALT up to 2 times the upper limit of normal, and excluded participants with cirrhosis, HCV, HIV, or HDV coinfection, eGFR at or below 60 mL/min/1.73 m2, or platelet count below 140 × 10⁹/L. Participants were randomized to bepirovirsen or placebo added to background NrtI therapy, with no active-comparator group. In the full analysis set, 92% of participants were HBeAg negative and 7% were enrolled in the US and Canada, and the label states that efficacy differences in participants aged 75 years and older “cannot be determined due to the small number of participants”. The label reports safety data for B-Well 1 and B-Well 2 only as pooled results, and neither the label nor the published abstract reports health-related quality of life or patient-reported outcome results.
Small number of participants aged 75 years and older
Exclusion of moderate or severe renal impairment
No data in hepatitis D virus coinfection or on transmission
Unknown clinical impact of binding-site variants with reduced susceptibility
B-Well 2
Objective
Purpose stated in the ClinicalTrials.gov brief summary
Main objective in the EU Clinical Trials Information System record
Main and secondary objectives in the EU Clinical Trials Register record
Aims of both B-Well trials stated by the company
Location and study date
Study dates and status in the ClinicalTrials.gov record
“Study Start (Actual) 2022-12-06” (opens the source at this quote in a new tab)
“Primary Completion (Actual) 2025-11-03” (opens the source at this quote in a new tab)
“Study Completion (Actual) 2026-04-13” (opens the source at this quote in a new tab)
“First Posted 2022-11-30” (opens the source at this quote in a new tab)
“Last Update Posted 2026-07-08” (opens the source at this quote in a new tab)
“Completed” (opens the source at this quote in a new tab)
“No Results Posted” (opens the source at this quote in a new tab)
Number of locations in the ClinicalTrials.gov record
Study locations by country in the ClinicalTrials.gov record
EU and EEA member states, trial start, and end of trial in the EU Clinical Trials Information System record
Planned sites in the European Economic Area and regulatory and ethics decisions in the EU Clinical Trials Register record
Countries in both B-Well trials stated by the company
Trial start in the company pipeline appendix
Initiation of the two phase 3 studies announced by the licensor
Study design
Official title in the ClinicalTrials.gov record
Design details in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Phase | “Phase 3” |
| Primary purpose | “Treatment” |
| Allocation | “Randomized” |
| Interventional model | “Parallel Assignment” |
| Model description | “This is a multicenter, randomized, double-blind, placebo-controlled study.” |
| Masking | “Quadruple” |
| Masking description | “This will be a double blinded study in which investigators/site staff and the Sponsor will remain blinded to treatment assignment.” |
Four study stages, stratification, and total duration in the ClinicalTrials.gov record
Two identically designed phase 3 trials in the prescribing information
Nucleos(t)ide analogue cessation at week 48 and cessation eligibility criteria
Criteria to restart nucleos(t)ide analogue therapy after cessation
Replicate double-blind design in the primary publication
“In two replicate, double-blind trials (B-Well 1 and B-Well 2), we randomly assigned adults with noncirrhotic chronic HBV infection in a 2:1 ratio to receive subcutaneous bepirovirsen (at a weekly dose of 300 mg) or placebo for 24 weeks.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“Eligible patients discontinued NA therapy at 48 weeks.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
Placebo control, treatment arms, and data monitoring committee in the EU Clinical Trials Register record
“Therapeutic confirmatory (Phase III) Yes” (opens the source at this quote in a new tab)
“Placebo Yes” (opens the source at this quote in a new tab)
“Number of treatment arms in the trial 2” (opens the source at this quote in a new tab)
“Trial has a data monitoring committee Yes” (opens the source at this quote in a new tab)
Design of both B-Well trials stated by the company
Eligibility criteria
Key inclusion and exclusion criteria summarized in the prescribing information
Population described in the primary publication
Inclusion criteria in the ClinicalTrials.gov record
Exclusion criteria: coinfection, cirrhosis, malignancy, vasculitis, and extrahepatic disorders in the ClinicalTrials.gov record
Exclusion criteria: prior and concomitant therapy in the ClinicalTrials.gov record
Definition of cirrhosis for exclusion in the EU Clinical Trials Register record
Other exclusion criteria in the EU Clinical Trials Register record
Treatment
Hibsago or placebo dosing regimen with background nucleos(t)ide analogue therapy
Arms and interventions in the ClinicalTrials.gov record
| Arm | Registry value |
|---|---|
| Experimental arm | “Experimental: Bepirovirsen”; “Bepirovirsen will be administered.” |
| Placebo arm | “Placebo Comparator: Placebo”; “Matching placebo will be administered.” |
Treatment arms in the company pipeline appendix
Investigational product and placebo in the EU Clinical Trials Register record
| Field | Registry value |
|---|---|
| Pharmaceutical form | “Solution for injection” |
| Route of administration | “Subcutaneous use” |
| Concentration unit | “mg/ml milligram(s)/millilitre” |
| Concentration number | “Concentration number 150” |
| Current sponsor code | “GSK3228836” |
| Placebo used | “Is a Placebo used in this Trial? Yes” |
| Pharmaceutical form of the placebo | “Pharmaceutical form of the placebo Solution for injection” |
| Route of administration of the placebo | “Route of administration of the placebo Subcutaneous use” |
| Care after the trial | “To continue with standard of care.” |
Study outcomes
Rationale for using functional cure as the primary endpoint
Registered primary outcome measure in the ClinicalTrials.gov record
Registered secondary outcome measures in the ClinicalTrials.gov record
Primary and secondary end points and time point in the EU Clinical Trials Register record
Primary and three key secondary endpoints assessed at week 72 in the prescribing information
Functional cure definition and assay thresholds in the company release
Functional cure definition and primary outcome in the primary publication
“Treatment with bepirovirsen, an antisense oligonucleotide targeting hepatitis B virus (HBV) transcripts, has the potential to result in a functional cure, defined by at least 24 weeks of a sustained HBV DNA level below the lower limit of quantification (LLOQ) and hepatitis B surface antigen (HBsAg) loss after fixed-duration therapy.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“The primary outcome was a functional cure at week 72.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
Functional cure as the preferred primary endpoint: AASLD-EASL treatment endpoints conference
“Of all these surrogate endpoints, HBsAg loss is considered to be the most relevant because HBsAg seroclearance is associated with sustained off-treatment improvement in clinical outcomes.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Moreover, HBsAg seroclearance is easy to measure with standardized and widely available assays.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“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
Clinical endpoints are unfeasible as trial endpoints: AASLD-EASL treatment endpoints conference
“These clinical endpoints however typically develop over decades and are therefore unfeasible to be used as primary therapeutic endpoints for clinical trials of new investigational agents.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Although long-term sustained off-treatment HBV DNA suppression is associated with similar improvements in clinical outcomes as HBsAg loss, in patients with cirrhosis, it is not reliably durable, and there is a 15-40% lifetime chance of disease reactivation.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Nucleos(t)ide analogue withdrawal in trial control arms: AASLD-EASL treatment endpoints conference
“If off-treatment response is a primary endpoint, then NA should be withdrawn from both active treatment and control arms but only if stringent predetermined criteria based on HBsAg levels and other parameters are met to ensure safety.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Efficacy endpoints and add-on placebo-controlled design for finite therapy: FDA guidance
Functional cure as the primary endpoint of phase II/III trials: EASL clinical practice guideline
Functional cure as the optimal endpoint for new therapies: bepirovirsen phase 2b design report
“Recently, functional cure, defined as durable hepatitis B surface antigen (HBsAg) loss with or without HBsAg seroconversion and undetectable HBV DNA, has been accepted as the optimal endpoint for new HBV therapies” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Functional cure is rare (≤ 5%) with NA therapy” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Statistical analysis description
Number of participants (Planned and analyzed)
Planned number of participants in the EU Clinical Trials Register record
“In the EEA 191” (opens the source at this quote in a new tab)
“In the whole clinical trial 900” (opens the source at this quote in a new tab)
“Number of subjects for this age range: 738” (opens the source at this quote in a new tab)
“Number of subjects for this age range: 162” (opens the source at this quote in a new tab)
Actual enrollment in the ClinicalTrials.gov record
Randomized participants and full analysis set in the prescribing information
Participants analyzed for the primary endpoint in the primary publication
Pooled B-Well 1 and B-Well 2 results: participants in both trials
Pooled B-Well 1 and B-Well 2 results: participants in the pooled safety population
Description of analysis sets
Statistical methods for the primary endpoint: stratified common rate difference and exact Cochran-Mantel-Haenszel test
Statistical methods for the key secondary endpoints in participants with baseline HBsAg up to 1,000 IU/mL
Ranked order of the primary and key secondary endpoints
Pooled B-Well 1 and B-Well 2 results: pooled safety data set, weeks 1 to 36
Pooled B-Well 1 and B-Well 2 results: subgroup analyses of the pooled population
Pooled B-Well 1 and B-Well 2 results: post hoc analysis of predictors of nonresponse
Pooled B-Well 1 and B-Well 2 results: durability population of participants who stopped nucleos(t)ide analogue therapy
Results
Participant disposition
Randomized participants and full analysis set
Baseline characteristics
Efficacy results
Primary and key secondary endpoints met
Primary endpoint: sustained HBV DNA suppression and HBsAg not detected 24 weeks after NrtI cessation, baseline HBsAg up to 3,000 IU/mL
| Measure (full analysis set) | Value |
|---|---|
| Hibsago, n/N (%) | “106/570 (19)” |
| Placebo, n/N (%) | “0/286 (0)” |
| Common rate difference, % (95% CI) | “13 (10.4, 16.1)” |
| p-value | “<0.0001” |
Key secondary endpoint: sustained HBV DNA suppression and HBsAg not detected, baseline HBsAg up to 1,000 IU/mL
| Measure (full analysis set) | Value |
|---|---|
| Hibsago, n/N (%) | “95/342 (28)” |
| Placebo, n/N (%) | “0/179 (0)” |
| Rate difference, % (95% CI) | “28 (23.3, 32.8)” |
| p-value | “<0.0001” |
Key secondary endpoints: sustained HBV DNA suppression below the LLOQ 24 weeks after NrtI cessation
| Measure (full analysis set) | Value |
|---|---|
| Baseline HBsAg up to 3,000 IU/mL: Hibsago, n/N (%) | “132/570 (23)” |
| Baseline HBsAg up to 3,000 IU/mL: placebo, n/N (%) | “0/286 (0)” |
| Baseline HBsAg up to 3,000 IU/mL: common rate difference, % (95% CI) | “18 (15.1, 21.3)” |
| Baseline HBsAg up to 1,000 IU/mL: Hibsago, n/N (%) | “113/342 (33)” |
| Baseline HBsAg up to 1,000 IU/mL: placebo, n/N (%) | “0/179 (0)” |
| Baseline HBsAg up to 1,000 IU/mL: rate difference, % (95% CI) | “33 (28.3, 38.2)” |
| p-value, each stratum | “<0.0001” |
Functional cure at week 72 by baseline HBsAg stratum, pooled and B-Well 2
| Population | Value |
|---|---|
| Pooled, baseline HBsAg up to 3,000 IU/mL: rate | “19% vs. 0% (placebo)” |
| Pooled, baseline HBsAg up to 3,000 IU/mL: participants | “233 of 1,220 vs. 0 of 614” |
| B-Well 2, baseline HBsAg up to 3,000 IU/mL: rate | “B-Well 2: 19% vs. 0%” |
| B-Well 2, baseline HBsAg up to 3,000 IU/mL: participants | “106 of 570 vs. 0 of 286” |
| Pooled, baseline HBsAg up to 1,000 IU/mL: rate | “26% vs. 0% (placebo)” |
| Pooled, baseline HBsAg up to 1,000 IU/mL: participants | “200 of 768 vs. 0 of 393” |
| B-Well 2, baseline HBsAg up to 1,000 IU/mL: rate | “B-Well 2: 28% vs. 0%” |
| B-Well 2, baseline HBsAg up to 1,000 IU/mL: participants | “95 of 342 vs. 0 of 179” |
Nucleotide polymorphisms in the bepirovirsen binding site
| Population and measure | Value |
|---|---|
| Baseline HBsAg up to 3,000 IU/mL: baseline polymorphisms, % (n/N) | “7 (7/104)” |
| Baseline HBsAg up to 3,000 IU/mL: treatment-emergent mutations, % (n/N) | “6 (2/31)” |
| Baseline HBsAg up to 1,000 IU/mL: baseline polymorphisms, % (n/N) | “12 (6/50)” |
| Baseline HBsAg up to 1,000 IU/mL: treatment-emergent mutations, % (n/N) | “0 (0/10)” |
Health-related quality of life and patient-reported outcomes
No evidence found.
Safety results
Safety data reported as pooled B-Well 1 and B-Well 2 results
Most frequently observed adverse events
Study limitations
Summary: study limitations
B-Well 2 had the same design as B-Well 1: bepirovirsen was administered for 24 weeks, the primary endpoint was assessed at week 72, 24 weeks after possible cessation of NrtI therapy, and the longest reported follow-up is week 96, covering the 295 of 1,220 pooled bepirovirsen recipients who stopped NrtI therapy at week 48. Eligibility required stable NrtI therapy, HBsAg above 100 and up to 3,000 IU/mL, HBV DNA below 90 IU/mL, and ALT up to 2 times the upper limit of normal, and excluded participants with cirrhosis, HCV, HIV, or HDV coinfection, eGFR at or below 60 mL/min/1.73 m2, or platelet count below 140 × 10⁹/L. Participants were randomized to bepirovirsen or placebo added to background NrtI therapy, with no active-comparator group. In the full analysis set, 92% of participants were HBeAg negative, 6% were enrolled in the US and Canada, and 2% had an unknown genotype. The label reports safety data for B-Well 1 and B-Well 2 only as pooled results, and neither the label nor the published abstract reports health-related quality of life or patient-reported outcome results.
Small number of participants aged 75 years and older
Exclusion of moderate or severe renal impairment
No data in hepatitis D virus coinfection or on transmission
Unknown clinical impact of binding-site variants with reduced susceptibility
B-Clear
Objective
Aim stated in the primary publication
Primary objective stated in the design publication
“The primary objective of the B-Clear study was to assess the efficacy of three dosing regimens of bepirovirsen: 24 weeks of treatment, 12 weeks of treatment with 12 weeks step-down dosing, and 12 weeks of treatment (with or without loading dose [LD]) in participants with chronic HBV infection on stable NA therapy or not currently receiving NA therapy.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Objective stated in the ClinicalTrials.gov record
Location and study date
Study dates and status in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Study start (actual) | “2020-07-27” |
| Primary completion (actual) | “2022-03-18” |
| Study completion (actual) | “2022-03-18” |
| First posted | “2020-06-26” |
| Results first posted | “2023-05-16” |
| Last update posted | “2023-05-16” |
| Status | “Completed” |
| Other study ID | “209668” |
Number of locations in the ClinicalTrials.gov record
Trial dates, sites, and countries in the primary publication
Sites enrolling both cohorts and last participant visit
“Investigators were able to recruit both On-NA and Not-on-NA participants to the same study; 68% (47/69) of sites had participants in both cohorts.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) and the last patient visit occurred in March 2022.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Presentation of end-of-study results
Study design
Phase 2b, randomized, investigator-unblinded parallel-cohort design
Design details in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Primary purpose | “Treatment” |
| Allocation | “Randomized” |
| Interventional model | “Parallel Assignment” |
| Interventional model description | “Participants with CHB will be divided into two different cohorts; participants on stable nucleos(t)ide treatment and participants not currently on nucleos(t)ide therapy. For each cohort, participants will be randomized into one of the 4 different parallel arms to receive treatment.” |
| Masking | “Single (Participant)” |
| Masking description | “Participants will be blinded to the study treatment.” |
| Phase | “Phase 2” |
Partial-blind design and screening period in the design publication
“B-Clear was a phase 2b, multicenter, randomized, partial blind (sponsor/participant-blinded, investigator-unblinded) parallel-cohort trial that enrolled people with chronic HBV infection receiving stable NA therapy (On-NA) and not currently receiving NA therapy (Not-on-NA).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Participants were followed for up to 55 weeks, including a screening period of up to 45 days, a 24-week treatment period, and a 24-week follow-up period (Fig. 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“As the primary endpoint was based on objective laboratory measurements (HBsAg and HBV DNA), unblinding of site staff would not compromise the assessment of this endpoint, although initiation of rescue medication based on the investigator’s judgment would result in failure to meet the endpoint.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Two cohorts combined in one protocol
“This trial administratively combined two studies in different HBV populations into one protocol, providing insight into the potential benefits of bepirovirsen for those on NA therapy and those not currently receiving NA therapy.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Placebo-first arm as a safety comparator
“Although no full placebo arm was included, arm 4 was intended to serve as a comparator of safety in the first 12 weeks of treatment, including exploratory analyses such as inflammatory and immune activation biomarkers. In addition, arm 4 enables assessment of 12-week active treatment without LD.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Rationale for unblinding site staff in the protocol
Protocol amendment 2: nucleos(t)ide analogue initiation during suspected flares
Eligibility criteria
Key eligibility criteria in the primary publication
Cohort definitions in the design publication
“Participants were included in the On-NA population if they had no changes in their NA regimen for ≥ 6 months before screening, with no planned changes to the regimen for the duration of the study, and had a HBsAg concentration > 100 IU/mL, HBV DNA concentration < 90 IU/mL, and ALT ≤ 2 × ULN.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Participants were included in the Not-on-NA population if they had either never received HBV treatment or ended NA therapy ≥ 6 months before screening or interferon-containing therapy ≥ 12 months before screening, and had a HBsAg concentration > 100 IU/mL, HBV DNA concentration > 2000 IU/mL, and ALT < 3 × ULN.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Inclusion criteria in the ClinicalTrials.gov record: HBsAg, HBV DNA, and ALT
Exclusion criteria in the ClinicalTrials.gov record: coinfection, cirrhosis, and hepatocellular carcinoma
Exclusion criteria in the ClinicalTrials.gov record: vasculitis, immune conditions, and prior therapy
Exclusion criteria in the ClinicalTrials.gov record: laboratory values and QTc
Age, sex, and healthy volunteers in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Ages eligible for study | “18 Years and older (Adult, Older Adult )” |
| Sexes eligible for study | “All” |
| Accepts healthy volunteers | “No” |
Treatment
Four regimens randomized 3:3:3:1
Injections per arm in the design publication
“Participants in arm 1 received bepirovirsen 300 mg (administered as two 150 mg injections) for 24 weeks, with a bepirovirsen 300 mg LD. In arm 2, participants received bepirovirsen 300 mg for 12 weeks, with a bepirovirsen 300 mg LD, then a step-down in dose to a single injection of 150 mg and a placebo injection for 12 weeks. In arm 3, participants received 12 weeks of bepirovirsen 300 mg, with a bepirovirsen 300 mg LD, then placebo (administered as two injections) for 12 weeks to maintain blinded treatment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“In arm 4, participants received placebo (administered as two injections) for 12 weeks (with a placebo LD) then bepirovirsen 300 mg without LD for 12 weeks.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Background nucleos(t)ide analogue therapy and criteria for initiating it
“Participants On-NA therapy at baseline were expected to continue their NA therapy without changes for the study duration. Participants not receiving NA therapy at baseline were expected to remain off NA throughout the study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“For these participants, NA therapy initiation was permitted if they had alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN; 40 IU/L [male participants] or 33 IU/L [female participants]) and bilirubin > 1.5 × ULN (18.81 µmol/L), and until other tests (e.g., HBV DNA, HBsAg) ruled out hepatitis B flare.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“NA therapy initiation was also permitted in arms 1–3 in case of virological breakthrough (defined as ≥ 1 log increase from nadir of HBV DNA or HBV DNA becoming quantifiable after being below the lower limit of quantification [LLOQ] at two sequential visits), virological non-response (< 1 log reduction in HBsAg by week 12) or partial response (> 1 log decline in HBV DNA, but subsequent plateau of HBV DNA levels such that achievement of HBV DNA below LLOQ was considered unlikely) to prevent development of resistance.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Study drug formulation in the ClinicalTrials.gov record
Rationale for the loading doses and the step-down regimen in the protocol
Study outcomes
Rationale for using sustained HBsAg and HBV DNA loss as the primary endpoint
Primary outcome definition and its purpose in the primary publication
Functional cure as the goal of therapy and its rarity with nucleos(t)ide analogues
Functional cure as the optimal endpoint: design publication
“While functional cure (durable undetectable hepatitis B virus [HBV] DNA and hepatitis B surface antigen [HBsAg] loss with or without HBsAg seroconversion) is the optimal endpoint for new chronic HBV therapies, this is rarely achieved with current standard of care despite long-term, sometimes often life-long, treatment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“While the optimal goal for new HBV therapies is both HBsAg and HBV DNA loss, most previous HBV studies have focused on assessment of HBV DNA levels only [12].” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Rescue medication and visit requirements for the primary endpoint
“Rescue medication was defined as any medication initiated for the purpose of suppressing HBV replication, including administration of NA in the Not-on-NA population. The response should be maintained at every visit (at least every 8 weeks) until 24 weeks after the end of bepirovirsen treatment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Interpretation of the endpoint in each cohort
“While this response cannot be considered equivalent to functional cure, as a result of the continuation of background NA therapy, it allowed determination of whether administration of bepirovirsen as an adjunct to NA therapy can increase the likelihood of functional cure.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Treatment outcomes for the Not-on-NA participants, who receive bepirovirsen monotherapy, established the potential for bepirovirsen to achieve functional cure and to become an additional option for standard of care treatment of people living with hepatitis B.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Clinically meaningful sustained virologic response with a finite course: protocol
Primary outcome measure in the ClinicalTrials.gov record
Modified primary outcome permitting blips
Secondary efficacy and safety outcomes
Statistical analysis description
Number of participants (Planned and analyzed)
Operating characteristics of the planned sample size
“For example, with a true response rate of 20%, the proposed sample size of n = 66 for arms 1–3 has approximately 70% probability of confirming a true response of at least 15%, and if the true rate is 30%, there is an 88% chance of confirming a true response of at least 20%. The lower bounds of 95% credible intervals excluded the historical placebo response of 3% if the observed response is ≥ 14% in arms 1–3 or 18% in arm 4.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Prior distribution in the protocol sample size determination
Participants analyzed in the primary publication
Enrollment in the ClinicalTrials.gov record
Description of analysis sets
Analysis sets defined in the statistical analysis plan
Primary estimand and handling of intercurrent events
Cohorts analyzed separately without multiplicity adjustment
Analysis populations in the ClinicalTrials.gov results
Results
Participant disposition
Discontinuation of the trial agent
Participant flow in the ClinicalTrials.gov results: groups 1 to 4 numbered as in the primary publication
| Participants | On NA, group 1 | On NA, group 2 | On NA, group 3 | On NA, group 4 | Not on NA, group 1 | Not on NA, group 2 | Not on NA, group 3 | Not on NA, group 4 |
|---|---|---|---|---|---|---|---|---|
| Started | “68” | “68” | “68” | “23” | “70” | “68” | “68” | “24” |
| Completed | “65” | “65” | “66” | “22” | “64” | “66” | “63” | “24” |
| Not completed | “3” | “3” | “2” | “1” | “6” | “2” | “5” | “0” |
| Adverse event | “0” | “1” | “1” | “0” | “1” | “0” | “1” | “0” |
| Lost to follow-up | “0” | “1” | “0” | “0” | “0” | “0” | “0” | “0” |
| Protocol violation | “0” | “1” | “0” | “0” | “0” | “0” | “0” | “0” |
| Physician decision | “0” | “0” | “0” | “0” | “0” | “1” | “0” | “0” |
| Withdrawal by participant | “3” | “0” | “1” | “1” | “5” | “1” | “4” | “0” |
Randomized participants who received no study treatment
Baseline characteristics
Demographic and clinical characteristics at baseline: intention-to-treat population, means ± SD
Nucleos(t)ide analogue therapy at baseline: participants receiving NA therapy
| Characteristic | Group 1 (N=68) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=23) |
|---|---|---|---|---|
| Current NA therapy for 3 years or more, no. (%) | “47 (69)” | “45 (67)” | “43 (63)” | “20 (87)” |
| Entecavir, no. (%) | “38 (56)” | “25 (37)” | “20 (29)” | “10 (43)” |
| Tenofovir disoproxil, no. (%) | “24 (35)” | “36 (54)” | “33 (49)” | “11 (48)” |
| Tenofovir alafenamide, no. (%) | “9 (13)” | “6 (9)” | “17 (25)” | “2 (9)” |
| Lamivudine, no. (%) | “1 (1)” | “1 (1)” | “1 (1)” | “0” |
Comparability of trial groups and upper limit of normal for ALT
Efficacy results
Primary outcome by group and cohort (intention-to-treat population)
| Result | On NA, group 1 (N=68) | On NA, group 2 (N=68) | On NA, group 3 (N=68) | On NA, group 4 (N=23) | Not on NA, group 1 (N=70) | Not on NA, group 2 (N=68) | Not on NA, group 3 (N=68) | Not on NA, group 4 (N=24) |
|---|---|---|---|---|---|---|---|---|
| Primary-outcome event, no. of participants (%) | “6 (9)” | “6 (9)” | “2 (3)” | “0” | “7 (10)” | “4 (6)” | “1 (1)” | “0” |
| Point estimate of response, % (95% credible interval) | “9 (0–31)” | “9 (0–43)” | “3 (0–16)” | “2 (0–8)” | “10 (0–38)” | “6 (0–25)” | “2 (0–6)” | “2 (0–8)” |
Primary outcome in the text of the primary publication
Primary outcome by baseline HBsAg level: group 1
HBsAg levels at the end of treatment and 24 weeks after: group 1
HBV DNA below the lower limit of quantification: participants not receiving NA therapy
HBsAg and HBV DNA below LLOQ at the end of treatment: ClinicalTrials.gov results
| Arm | Participants analyzed | Participants with response | Percentage |
|---|---|---|---|
| On NA, group 1 | “68” | “16” | “23.5%” |
| On NA, group 2 | “68” | “9” | “13.2%” |
| On NA, group 3 | “68” | “8” | “11.8%” |
| On NA, group 4 | “23” | “4” | “17.4%” |
| Not on NA, group 1 | “70” | “17” | “24.3%” |
| Not on NA, group 2 | “68” | “10” | “14.7%” |
| Not on NA, group 3 | “68” | “6” | “8.8%” |
| Not on NA, group 4 | “24” | “1” | “4.2%” |
Median time to ALT normalization in participants with baseline ALT above ULN: ClinicalTrials.gov results
| Arm | Participants analyzed | Median, weeks | 95% confidence interval |
|---|---|---|---|
| On NA, group 1 | “6” | “16.6” | “(1.1 to NA)” |
| On NA, group 2 | “7” | “4.1” | “(1.0 to 11.9)” |
| On NA, group 3 | “6” | “1” | “(1.0 to 8.1)” |
| On NA, group 4 | “2” | “7” | “(1.1 to NA)” |
| Not on NA, group 1 | “20” | “13.4” | “(2.1 to NA)” |
| Not on NA, group 2 | “20” | “15.1” | “(4.3 to 18.1)” |
| Not on NA, group 3 | “21” | “10.7” | “(5.1 to 21.1)” |
| Not on NA, group 4 | “9” | “18.1” | “(1 to 32.1)” |
Bepirovirsen pharmacokinetics in participants receiving NA therapy: ClinicalTrials.gov results
| Parameter | Bepirovirsen 150 mg (n=12) | Bepirovirsen 300 mg (n=12) |
|---|---|---|
| AUC0-24h, h*ug/mL, mean (SD) | “55.214(22.9901)” | “140.312(37.3548)” |
| Cmax, ug/mL, mean (SD) | “6.112(2.8112)” | “14.956(5.6592)” |
| Tmax, hour, median | “3.008” | “3.017” |
| Tmax, hour, full range | “(2.00 to 4.02)” | “(2.00 to 5.00)” |
Bepirovirsen terminal half-life: ClinicalTrials.gov results
| Arm | Participants analyzed | Median, days | Full range |
|---|---|---|---|
| On NA, group 1 | “68” | “28.897” | “(7.52 to 191.98)” |
| On NA, group 2 | “67” | “24.918” | “(8.84 to 216.43)” |
| Not on NA, group 1 | “70” | “27.846” | “(10.19 to 149.74)” |
| Not on NA, group 2 | “67” | “38.205” | “(6.87 to 161.83)” |
Primary outcome and low-baseline-HBsAg subgroup in the company release
Health-related quality of life and patient-reported outcomes
Patient-reported outcome objective and instruments planned in the protocol
Patient-reported outcome results
No evidence found.
Safety results
Safety summary by group and cohort: safety population, number of participants (percent)
Adverse events during weeks 1 through 12, when a placebo comparison was possible
Adverse events during weeks 1 through 48
ALT increases of 3 times ULN or more
Serious adverse events, other adverse events, and deaths: ClinicalTrials.gov results, affected participants at risk up to week 48
| Event | On NA, group 1 | On NA, group 2 | On NA, group 3 | On NA, group 4 | Not on NA, group 1 | Not on NA, group 2 | Not on NA, group 3 | Not on NA, group 4 |
|---|---|---|---|---|---|---|---|---|
| All-cause mortality | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Serious adverse events, total | “1/68 (1.47%)” | “1/67 (1.49%)” | “4/68 (5.88%)” | “0/23 (0.00%)” | “6/70 (8.57%)” | “2/67 (2.99%)” | “3/68 (4.41%)” | “0/24 (0.00%)” |
| Other (not serious) adverse events, total | “56/68 (82.35%)” | “59/67 (88.06%)” | “53/68 (77.94%)” | “16/23 (69.57%)” | “65/70 (92.86%)” | “60/67 (89.55%)” | “61/68 (89.71%)” | “19/24 (79.17%)” |
| Thrombocytopenia (not serious) | “4/68 (5.88%)” | “2/67 (2.99%)” | “1/68 (1.47%)” | “0/23 (0.00%)” | “5/70 (7.14%)” | “2/67 (2.99%)” | “3/68 (4.41%)” | “0/24 (0.00%)” |
Individual serious adverse events: ClinicalTrials.gov results
Study limitations
Summary: study limitations
B-Clear had no full placebo arm: group 4 received placebo only during weeks 1 through 12, enrolled 23 participants receiving NA therapy and 24 not receiving it, and was not powered for the primary outcome. The primary outcome was analyzed by estimation without hypothesis testing or adjustment for multiplicity, the 95% credible intervals in group 1 spanned 0 to 31 in participants receiving NA therapy and 0 to 38 in those not receiving it, and some estimates came from a post hoc unstratified analysis because the prespecified Bayesian model did not converge. Investigators knew the trial-group assignments, while the sponsor and participants were blinded. Response was assessed for 24 weeks after the end of treatment, and in the cohort that continued NA therapy the response “cannot be considered equivalent to functional cure”. Generalizability is limited by the inclusion criteria, which excluded participants with cirrhosis, hepatocellular carcinoma, or hepatitis C, HIV, or hepatitis D coinfection.
No full placebo arm and small placebo-first arm
“A full placebo arm was not included in the study on the basis of feedback from external experts and a focus group of patients with chronic HBV infection, who expressed concerns owing to the study burden. Therefore, all participants received active treatment with bepirovirsen. The absence of a full placebo arm limits interpretation of the results, preventing direct comparison with a group that received no treatment” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The size of arm 4 does limit interpretation of the LD requirement. This arm was originally planned to be a placebo-only arm and hence had a lower sample size; following the change in treatment regimen that occurred on the basis of protocol feedback, the sample size was not increased. Hence further investigations may be required to assess the need for a LD.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Limited off-treatment follow-up and generalizability
“Although conclusions from the B-Clear study were limited to the 24-week off-treatment period for most treatment arms, except for arm 3 which includes a 36-week off-treatment follow-up period, longer-term open-label data will be collected in the B-Sure extension study mentioned above, to evaluate the durability of response. Generalizability of the data to the wider population of people living with chronic HBV infection is limited to the requirements for study inclusion.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Authors' statements on the size of the effect and the need for larger trials
B-Sure
Objective
Objective stated in the ClinicalTrials.gov record
Official title in the ClinicalTrials.gov record
Aim stated on the first annual report poster
Durability follow-up described in the B-Clear publications
Durability follow-up described in the company release of B-Clear results
Location and study date
Study dates and status in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Study start (actual) | “2021-12-14” |
| Primary completion (estimated) | “2029-01-24” |
| Study completion (estimated) | “2029-01-24” |
| First posted | “2021-07-08” |
| Last update posted | “2026-06-24” |
| Status | “Active, not recruiting” |
| Other study IDs | “206882” |
| EU CT number | “2023-506867-33” |
Number of locations in the ClinicalTrials.gov record
Congress presentations of interim data
Study design
Design details in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Study type | “Interventional” |
| Phase | “Phase 2” |
| Primary purpose | “Treatment” |
| Allocation | “Non-Randomized” |
| Interventional model | “Parallel Assignment” |
| Masking | “None (Open Label)” |
Follow-up duration by arm
Response categories and follow-up schedule: B-Clear responders
Follow-up schedule after nucleos(t)ide analogue cessation: B-Clear On-NA responders
Durability assessment in the first annual report
Eligibility criteria
General inclusion and exclusion criteria in the ClinicalTrials.gov record
Inclusion criteria for participants rolling over from B-Clear, B-Together, and B-Fine
Inclusion criteria for participants rolling over from B-Well 1 and B-Well 2
Criteria for nucleos(t)ide analogue discontinuation and restart: B-Clear On-NA responders
Age, sex, and healthy volunteers in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Ages eligible for study | “18 Years and older (Adult, Older Adult )” |
| Sexes eligible for study | “All” |
| Accepts healthy volunteers | “No” |
Treatment
No study treatment administered
Nucleos(t)ide analogue cessation 3 months after entry
Study outcomes
Rationale for using durability of functional cure as the primary endpoint
Primary outcome measures in the ClinicalTrials.gov record
Functional cure as the optimal endpoint
Time off treatment required before a response counts as functional cure: Not-on-NA participants
Time off treatment required before a response counts as functional cure: On-NA participants
Functional cure rarely achieved with nucleos(t)ide analogues: first annual report
Secondary outcome measures: relapse, retreatment, and delayed functional cure
Statistical analysis description
Number of participants (Planned and analyzed)
Planned enrollment in the ClinicalTrials.gov record
B-Clear complete responders enrolled: first annual report
B-Clear Not-on-NA responders enrolled: third report
B-Clear On-NA responders enrolled: third report
Description of analysis sets
Complete responders by the modified primary outcome: first annual report
Participants enrolled in error and excluded from the flow analysis: Not-on-NA
Participants enrolled in error and reclassification after blips: On-NA
Results
Participant disposition
Disposition of B-Clear On-NA complete responders: first annual report
Time from B-Clear end of study to B-Sure entry: Not-on-NA, first annual report
Disposition of B-Clear On-NA responders: third report
Baseline characteristics
B-Clear complete responders enrolled in B-Sure: first annual report
| Characteristic at B-Clear baseline | On-NA (N=13) | Not-on-NA (N=12) |
|---|---|---|
| Male, n (%) | “12 (92)” | “7 (58)” |
| Age, mean (SD) years | “53.20 (10.01)” | “43.80 (9.96)” |
| B-Clear arm 1, n (%) | “7 (54)” | “7 (58)” |
| B-Clear arm 2, n (%) | “5 (38)” | “4 (33)” |
| B-Clear arm 3, n (%) | “1 (8)” | “1 (8)” |
| HBeAg negative, n (%) | “10 (77)” | “12 (100)” |
| HBeAg positive, n (%) | “3 (23)” | “0” |
| HBsAg 1000 IU/mL or less, n (%) | “9 (69)” | “7 (58)” |
| HBsAg more than 1000 to 3000 IU/mL, n (%) | “3 (23)” | “3 (25)” |
| HBsAg more than 3000 IU/mL, n (%) | “1 (8)” | “2 (17)” |
B-Clear Not-on-NA participants enrolled in B-Sure: third report
| Characteristic at B-Clear baseline | All participants (N=17) |
|---|---|
| Age, mean (SD) years | “44.1 (10.4)” |
| B-Clear arm 1, n (%) | “9 (53)” |
| B-Clear arm 2, n (%) | “6 (35)” |
| B-Clear arm 3, n (%) | “2 (12)” |
| B-Clear arm 4, n (%) | “0 (0)” |
| HBeAg negative, n (%) | “17 (100)” |
| HBsAg 1000 IU/mL or less, n (%) | “9 (53)” |
| HBsAg more than 1000 to 3000 IU/mL, n (%) | “4 (24)” |
| HBsAg more than 3000 IU/mL, n (%) | “4 (24)” |
| HBV DNA 4 log10 IU/mL or less, n (%) | “7 (41)” |
| HBV DNA more than 4 to 6 log10 IU/mL, n (%) | “9 (53)” |
| HBV DNA more than 6 log10 IU/mL, n (%) | “1 (6)” |
B-Clear On-NA participants enrolled in B-Sure: third report
| Characteristic at B-Clear baseline | All participants (N=44) |
|---|---|
| Age, mean (SD) years | “53.8 (11.4)” |
| B-Clear arm 1, n (%) | “21 (48)” |
| B-Clear arm 2, n (%) | “15 (34)” |
| B-Clear arm 3 or arm 4, n (%) each | “4 (9)” |
| Probable duration of chronic HBV infection less than 10 years, n (%) | “11 (25)” |
| Probable duration 10 to less than 20 years, n (%) | “14 (32)” |
| Probable duration 20 years or more, n (%) | “19 (43)” |
| HBeAg negative, n (%) | “34 (77)” |
| HBeAg positive, n (%) | “10 (23)” |
| HBsAg more than 100 to 1000 IU/mL, n (%) | “32 (73)” |
| HBsAg more than 1000 to 3000 IU/mL, n (%) | “10 (23)” |
| HBsAg more than 3000 IU/mL, n (%) | “2 (5)” |
Efficacy results
Durability in B-Clear Not-on-NA responders: third report
Durability in B-Clear On-NA responders after nucleos(t)ide analogue cessation: third report
Durability in B-Clear complete responders: first annual report
Sub-analysis of B-Together responders announced for AASLD 2025 (no figures released)
Health-related quality of life and patient-reported outcomes
No evidence found.
Safety results
No latent adverse drug effect: first annual report
ALT increases after nucleos(t)ide analogue cessation: B-Clear On-NA responders, third report
Safety in B-Clear Not-on-NA responders: third report
Study limitations
Summary: study limitations
B-Sure is open-label and non-randomized and enrolls only participants who responded in a parent study, so it has no comparator group and its durability estimates describe responders. As of October 2026, the B-Sure results available for B-Clear participants are congress posters with small denominators: 13 On-NA and 12 Not-on-NA complete responders in the first annual report, and 44 On-NA and 17 Not-on-NA enrolled participants in the third report. The first report's authors stated that the data should be interpreted with caution owing to low participant numbers. In the third report, participants were reclassified after reconsideration of how to handle blips, 1 Not-on-NA and 4 On-NA non-responders were enrolled in error, and only 6 of the 8 Not-on-NA participants with functional cure had reached Month 27 at the 9 September 2024 data cut-off. The ClinicalTrials.gov record has no posted results, and its estimated primary completion date is 24 January 2029.
Small numbers stated by the authors of the first annual report
Benefit in partial responders not yet established
Open-label, non-randomized design in the ClinicalTrials.gov record
| Field | Registry value |
|---|---|
| Allocation | “Non-Randomized” |
| Masking | “None (Open Label)” |
| Results | “No Results Posted” |
B-Together
Objective
Primary aim: whether sequential bepirovirsen and Peg-IFN reduces relapse and improves response
Hypothesis: conversion of partial responders and prevention of relapse
Questions the protocol was designed to answer
Secondary and exploratory objectives
Location and study date
Registry record: identifiers, dates, and enrollment
| Field | Quoted record |
|---|---|
| Other study identifier | “209348” |
| Study start (actual) | “2021-01-28” |
| Primary completion (actual) | “2023-02-17” |
| Enrollment (actual) | “108” |
| Number of listed locations | “This study has 49 locations” |
| Results first posted | “2024-05-02” |
Overlap of sites with B-Clear
Study design
Phase IIb, multicentre, randomised, open-label design
Randomisation, stratification, and allocation concealment
Registered design details
| Field | Quoted record |
|---|---|
| Allocation | “Randomized” |
| Interventional model | “Parallel Assignment” |
| Masking | “None (Open Label)” |
| Model description | “Participants will be randomised in a ratio of 1:1 to one of two treatment arms: 24 weeks GSK3228836 followed by up to 24 weeks PegIFN, or 12 weeks GSK3228836 followed by up to 24 weeks PegIFN.” |
Rationale for enrolling participants controlled on NA therapy
Eligibility criteria
Key inclusion and exclusion criteria
Age range and registered inclusion criteria
Cirrhosis exclusion
Exclusions related to interferon, psychiatric history, and prior oligonucleotides
Treatment
Bepirovirsen dose and duration followed by Peg-IFN
Registered arms
Rationale for 24 weeks of Peg-IFN rather than 48 weeks
Study outcomes
Rationale for using sustained HBsAg and HBV DNA loss 24 weeks after sequential treatment as the primary endpoint
Post hoc alternative primary outcome and definition of relapse
Functional cure as the endpoint for new HBV therapies
Protocol rationale for sustained virologic response
Safety outcomes and adverse events of special interest
Statistical analysis description
Number of participants (Planned and analyzed)
Planned enrollment and Bayesian sample size basis
Participants enrolled and analyzed
Participants contributing to the biomarker analysis
Description of analysis sets
Primary analysis model and its simplification
Handling of wide disruptive events such as COVID-19
Protocol definitions of analysis populations
| Population | Quoted description |
|---|---|
| Intent-to-treat | “All randomised participants.” |
| Safety | “All participants who were randomised and received at least one dose of study treatment” |
| Multiplicity | “No adjustments will be made for multiplicity.” |
Biomarker analysis population and response subgroups
“All B-Together randomized participants from the rest of the world population (excluding China), who had been assessed for the primary outcome and who received at least one dose of bepirovirsen treatment and ≥ 12 doses of Peg-IFN were included in biomarker analyses [8].” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Null responders were non-responders who did not have two or more consecutive visits with a > 0.4 log10 HBsAg reduction while on treatment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Results
Participant disposition
Withdrawals, Peg-IFN eligibility, and missed visits
Registry participant flow
| Disposition | Arm 1 (24 weeks bepirovirsen) | Arm 2 (12 weeks bepirovirsen) |
|---|---|---|
| Started | “55” | “53” |
| Completed | “49” | “50” |
| Not completed | “6” | “3” |
| Reason not completed: adverse event | “2” | “0” |
| Reason not completed: lost to follow-up | “1” | “0” |
| Reason not completed: physician decision | “0” | “1” |
| Reason not completed: withdrawal by subject | “3” | “2” |
Missed doses due to wide disruptive events
Baseline characteristics
Baseline HBsAg level and HBeAg status: most participants above 1,000 IU/ml and HBeAg negative
Baseline demographics and disease characteristics
| Characteristic | Arm 1 (n = 55) | Arm 2 (n = 53) | Overall (N = 108) |
|---|---|---|---|
| Age, mean (SD), years | “45.5 (10.7)” | “45.5 (9.4)” | “45.5 (10.0)” |
| Female, n (%) | “11 (20)” | “20 (38)” | “31 (29)” |
| Male, n (%) | “44 (80)” | “33 (62)” | “77 (71)” |
| Asian, n (%) | “30 (55)” | “26 (49)” | “56 (52)” |
| Black or African American, n (%) | “3 (5)” | “3 (6)” | “6 (6)” |
| White, n (%) | “22 (40)” | “24 (45)” | “46 (43)” |
| BMI, mean (SD), kg/m2 | “23.7 (3.4)” | “25.0 (4.2)” | “24.3 (3.9)” |
| HBsAg, mean (SD), IU/ml | “5,231.4 (8,939.8)” | “5,218.5 (8,437.4)” | “5,225.1 (8,656.2)” |
| HBsAg ≤1,000 IU/ml, n (%) | “17 (31)” | “17 (32)” | “34 (31)” |
| HBsAg >1,000 IU/ml, n (%) | “38 (69)” | “36 (68)” | “74 (69)” |
| HBV DNA <LLOQ, n (%) | “49 (89)” | “48 (91)” | “97 (90)” |
| HBeAg negative, n (%) | “41 (75)” | “39 (74)” | “80 (74)” |
| HBeAg positive, n (%) | “14 (25)” | “14 (26)” | “28 (26)” |
| TAF or TDF, n (%) | “33 (61)” | “37 (70)” | “70 (65)” |
| Entecavir, n (%) | “19 (35)” | “12 (23)” | “31 (29)” |
| ALT ≤ULN, n (%) | “51 (93)” | “43 (81)” | “94 (87)” |
| ALT >ULN, n (%) | “4 (7)” | “10 (19)” | “14 (13)” |
| HBV genotype undetermined, n (%) | “28 (51)” | “26 (49)” | “54 (50)” |
| METAVIR fibrosis score available, n | “7” | “8” | “15” |
Efficacy results
Primary outcome: 5 of 55 participants in Arm 1 and 8 of 53 in Arm 2
Primary outcome by baseline HBsAg and HBeAg stratum
| Stratum | Arm 1 n | Arm 1 responders, n (%) | Arm 2 n | Arm 2 responders, n (%) |
|---|---|---|---|---|
| Stratum 1: HBsAg ≤1,000 IU/ml, HBeAg negative | “16” | “3 (19)” | “14” | “7 (50)” |
| Stratum 2: HBsAg >1,000 IU/ml, HBeAg negative | “25” | “1 (4)” | “25” | “1 (4)” |
| Stratum 3: HBsAg ≤1,000 IU/ml, HBeAg positive | “1” | “1 (100)” | “3” | “0” |
| Stratum 4: HBsAg >1,000 IU/ml, HBeAg positive | “13” | “0” | “11” | “0” |
Registry primary outcome and between-arm comparison
Baseline HBsAg threshold among responders
Predictors of response in the logistic regression model
Odds ratios for response by baseline HBsAg, treatment arm, and NA type
| Comparison | Responders in reference group, n/N (%) | Responders in comparison group, n/N (%) | Odds ratio (95% CI) | p value |
|---|---|---|---|---|
| Baseline HBsAg >1,000 versus ≤1,000 IU/ml | “11/34 (32.4)” | “2/73 (2.7)” | “0.05 (0.00, 0.26)” | “<0.0001” |
| Arm 2 versus Arm 1 | “5/54 (9.3)” | “8/53 (15.1)” | “1.01 (0.17, 5.96)” | “0.99” |
| Entecavir versus TAF and TDF | “10/70 (14.3)” | “2/31 (6.5)” | “0.09 (0.01, 0.61)” | “0.0119” |
| HBeAg positive versus negative | “12/79 (15.2)” | “1/28 (3.6)” | “0.28 (0.01, 3.27)” | “0.3263” |
Response and relapse at the end of each treatment window
Peg-IFN did not convert partial responders
Indirect comparison of relapse with B-Clear
Durability of primary outcome response in Arm 2
HBeAg loss and anti-HBe seroconversion
Comparison of bepirovirsen treatment durations
Median time to ALT normalization in participants with baseline ALT above ULN
| Measure | Arm 1 | Arm 2 |
|---|---|---|
| Participants analyzed | “4” | “10” |
| Median, weeks | “not estimable (NE)” | “4.1” |
| 95% CI, weeks | “(6.3 to NA)” | “(1.1 to 47.1)” |
Peripheral immune activation and markers of hepatocyte death
“Increases from baseline in mean expression of serum proteins with immune effector and apoptotic functions (Week 3) and transcripts associated with immune cell proliferation and activation (Week 5) were observed regardless of arm or response subgroup. By Week 8, serum liver and apoptosis-specific proteins were increased; this was more pronounced in responders than non-responders, with the difference more marked in Arm 1 versus Arm 2. Increased abundance of these proteins was highly correlated with ALT levels, which were often associated with transient hepatitis B virus (HBV) DNA elevations and HBsAg decreases.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Longer-term follow-up of responders in B-Sure
Follow-up of responders planned in B-Sure
Health-related quality of life and patient-reported outcomes
No evidence found.
Safety results
Overall adverse events, discontinuations, serious adverse events, and deaths
Adverse events over the whole study
| Event, n (%) | Arm 1 (n = 55) | Arm 2 (n = 53) | Total (N = 108) |
|---|---|---|---|
| Any AE | “52 (95)” | “52 (98)” | “104 (96)” |
| Any AE related to study treatment | “52 (95)” | “48 (91)” | “100 (93)” |
| AEs leading to permanent discontinuation | “2 (4)” | “2 (4)” | “4 (4)” |
| Any grade 3 and 4 event | “31 (56)” | “23 (43)” | “54 (50)” |
| Any SAE | “6 (11)” | “2 (4)” | “8 (7)” |
| AESI: ALT increase | “27 (49)” | “11 (21)” | “38 (35)” |
| AESI: vascular inflammation and complement activation | “19 (35)” | “11 (21)” | “30 (28)” |
| AESI: thrombocytopenia | “29 (53)” | “19 (36)” | “48 (44)” |
| AESI: renal injury | “10 (18)” | “7 (13)” | “17 (16)” |
| Neutropenia | “10 (18)” | “12 (23)” | “22 (20)” |
| Leukopenia | “10 (18)” | “7 (13)” | “17 (16)” |
Adverse events during the bepirovirsen treatment window
| Event, n (%) | Arm 1 (n = 55) | Arm 2 (n = 53) | Total (N = 108) |
|---|---|---|---|
| Any AE | “48 (87)” | “42 (79)” | “90 (83)” |
| Any AE related to study treatment | “47 (85)” | “39 (74)” | “86 (80)” |
| AEs leading to permanent discontinuation | “1 (2)” | “2 (4)” | “3 (3)” |
| Any grade 3 and 4 event | “20 (36)” | “16 (30)” | “36 (33)” |
| Any SAE | “4 (7)” | “1 (2)” | “5 (5)” |
| AESI: ALT increase | “16 (29)” | “8 (15)” | “24 (22)” |
| AESI: vascular inflammation and complement activation | “16 (29)” | “6 (11)” | “22 (20)” |
| AESI: thrombocytopenia | “11 (20)” | “7 (13)” | “18 (17)” |
| AESI: renal injury | “10 (18)” | “6 (11)” | “16 (15)” |
Adverse events during the Peg-IFN treatment window
ALT increases and the serious adverse event of drug-induced liver injury
Grade 3 and 4 events and DAIDS laboratory grading
Registry serious and selected other adverse events through Week 72
| Event, affected / at risk (%) | Arm 1 | Arm 2 |
|---|---|---|
| All-cause mortality | “0/55 (0.00%)” | “0/53 (0.00%)” |
| Serious adverse events, total | “6/55 (10.91%)” | “2/53 (3.77%)” |
| Other adverse events, total | “52/55 (94.55%)” | “50/53 (94.34%)” |
| Injection site erythema | “20/55 (36.36%)” | “22/53 (41.51%)” |
| Pyrexia | “17/55 (30.91%)” | “14/53 (26.42%)” |
| Alanine aminotransferase increased | “23/55 (41.82%)” | “6/53 (11.32%)” |
| Thrombocytopenia | “14/55 (25.45%)” | “11/53 (20.75%)” |
| Influenza like illness | “12/55 (21.82%)” | “8/53 (15.09%)” |
| COVID-19 (non-serious) | “15/55 (27.27%)” | “5/53 (9.43%)” |
Study limitations
Summary: study limitations
B-Together randomized 108 participants (55 to 24 weeks and 53 to 12 weeks of bepirovirsen, each followed by up to 24 weeks of Peg-IFN) and had no bepirovirsen-only control arm, so the effect of adding Peg-IFN was assessed by indirect comparison with B-Clear. Treatment was open label, the sample size of approximately 100 was selected to provide a 65% posterior probability of the true response rate exceeding a fixed threshold, and the 95% credible intervals for the primary outcome were 0 to 46% in Arm 1 and 0 to 56% in Arm 2. COVID-19 infections and lockdowns caused missed visits for 9 participants, all in Arm 1. All primary outcome responders had baseline HBsAg of 3,000 IU/ml or lower, and the approved label recommends against concomitant administration of bepirovirsen with peginterferon alfa-2a. GSK funded the trial and took part in its design, conduct, and analysis, and authors employed by GSK hold financial equities in GSK.
Absence of a bepirovirsen-only control group
Effect of the COVID-19 pandemic on Arm 1
Small arms and heterogeneity limit between-arm comparison
Limitations of the post hoc biomarker analysis
“These analyses were opportunistic and not powered.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Second, all patients in B-Together received bepirovirsen, and findings could not be validated against a placebo-treated population within this study. Third, due to limited PBMC availability, this study could not demonstrate activation of HBV-specific T and B cells in the liver or periphery.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Finally, due to operational complexities, this study did not include liver sampling, which would have been required to show direct evidence of killing of infected hepatocytes.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Applicability: label recommendation on peginterferon alfa-2a
Funding, sponsor role, and author employment
ISIS 505358-CS3 phase 2a study
Objective
Primary and secondary objectives
“The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
First evaluation of an antisense oligonucleotide targeting HBV RNA in patients
“This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Exploratory objective: seroconversion
“Exploratory endpoints and objectives included describing the rate of seroconversion to anti-HBs or anti-HBe antibody-positive during treatment with bepirovirsen and then during subsequent treatment with TDF, or ETV if administered (proportion of patients with antibody positivity at day 29 and at week 31).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Location and study date
Centers and enrollment period
“Patients were enrolled from one center in Hong Kong and five centers in the Republic of Korea. The first patient was enrolled on 22 February 2017, the last patient was enrolled on 30 April 2019, the last patient visit was on 18 December 2019 and the study was completed on 19 December 2019.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registry record: identifiers, dates, and locations
| Field | Quoted record |
|---|---|
| GSK study identifier | “205695” |
| Ionis study identifier | “ISIS 505358-CS3” |
| Study start (actual) | “2017-02-24” |
| Primary completion (actual) | “2019-12-18” |
| Study completion (actual) | “2019-12-26” |
| Enrollment (actual) | “31” |
| Number of listed locations | “This study has 7 locations” |
Sponsorship at the time of the trial
Study design
Phase 2, double-blinded, placebo-controlled, dose-escalation design
“The ISIS 505358-CS3 study (GSK study 205695; ClinicalTrials.gov: NCT02981602) was a phase 2, double-blinded, placebo-controlled, dose-escalation trial of bepirovirsen in 31 patients with CHB who were either treatment-naïve (cohorts 1–3, n = 24) or receiving stable NA therapy (cohort 4 (on-NA), n = 7) (Supplementary Fig. 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Randomization and blinding
“Patients were randomized (3:1 within each dose cohort) to bepirovirsen or placebo according to the randomization schedule (permuted block).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“All participants, study monitors, study center personnel and contract research organization personnel were blinded to treatment assignment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Dose escalation and the decision to repeat 300 mg in cohort 3
“Although the Data and Safety Monitoring Board supported dose escalation to 450 mg, it was acknowledged that further evaluation of the 300 mg dose was warranted and the sponsor continued evaluation of the 300 mg dose in the third cohort to allow further characterization of the antiviral effect of bepirovirsen at the 300 mg dose level. One exploratory cohort was added to evaluate add-on treatment with bepirovirsen 300 mg versus placebo in on-NA patients with CHB.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Protocol amendment adding the on-NA cohort
“The amendment, implemented after study initiation and demonstration of the drug’s antiviral effect in treatment naïve patients, was introduced to determine whether antiviral effects could be observed in patients receiving stable NA therapy.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registered design details
| Field | Quoted record |
|---|---|
| Allocation | “Randomized” |
| Interventional model | “Parallel Assignment” |
| Masking | “Triple (ParticipantInvestigatorOutcomes Assessor)” |
| Placebo | “Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator” |
Eligibility criteria
Key inclusion criteria
“Inclusion criteria were chronic HBV infection ≥6 months and serum HBsAg ≥50 IU ml−1; both HBeAg-positive and HBeAg-negative patients could participate. Treatment-naïve patients had a plasma HBV DNA ≥2 × 103 IU ml−1. On-NA patients had HBV DNA adequately suppressed (plasma or serum HBV DNA below LLOQ (20 IU ml−1)), were taking stable TDF or ETV for ≥12 months and expected to continue taking stable TDF or ETV without change through to the end of their participation in this study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Key exclusion criteria
“Exclusion criteria were: a history of liver cirrhosis and/or evidence of cirrhosis, liver failure, liver disease other than hepatitis B, Gilbert’s syndrome or history of laboratory results consistent with Gilbert’s syndrome, extrahepatic disorders possibly related to HBV immune complexes, excess alcohol consumption; co-infection with hepatitis C virus, hepatitis D virus or HIV; screening laboratory values of ALT and AST >5× ULN.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Treatment
Dosing schedule and follow-up
“Treatment-naïve patients were randomized to placebo (n = 6), bepirovirsen 150 mg (n = 6) or 300 mg (n = 12) and on-NA patients to placebo (n = 2) or bepirovirsen 300 mg (n = 5) (Supplementary Fig. 2). Six doses of bepirovirsen or placebo were administered via subcutaneous injection during the 4-week treatment period: twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Patients were then followed for 26 weeks.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Loading doses and nucleos(t)ide analogue treatment after day 29
“Twice weekly dosing in weeks 1 and 2 constituted loading doses, with the aim of reaching steady-state hepatic concentrations following the week 3 dose (that is, before the last dose in the schedule) instead of 13–15 weeks without loading.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“After these assessments, all patients received daily treatment with NA to end of study (week 31; day 211). Patients already on a stable NA regimen (on-NA) received treatment throughout (during all study periods).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registered administration by cohort
Study outcomes
Rationale for using adverse events and clinical laboratory assessments as the primary endpoints
Primary safety endpoints
“The primary objective of the study was to examine the safety and tolerability of bepirovirsen administration in treatment-naïve participants with CHB infection (primary endpoints were AEs, clinical laboratory tests, vital signs and body weight, physical examination, electrocardiogram and concomitant medication usage).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
No primary efficacy endpoint in the protocol
Secondary antiviral endpoints
“Secondary objectives and endpoints were to: examine the effects of bepirovirsen administration on plasma HBV DNA concentration (change from baseline to day 29 and week 31); examine the effects of bepirovirsen administration on serum HBsAg concentration (change from baseline to day 29 and week 31, proportion of participants with HBsAg loss at day 29 and at week 31)” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Rationale for HBsAg as the antiviral measure
“The treatment goal for patients with CHB is to obtain functional cure, namely, sustained loss of detectable serum HBsAg with undetectable HBV DNA” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Functional cure is associated with improved clinical outcomes and allows patients to be off-therapy with a minimal risk of relapse” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Protocol background on HBsAg loss as the treatment endpoint
Day 29 as the time of antiviral assessment
Dose-limiting toxicity definition
Statistical analysis description
Number of participants (Planned and analyzed)
Sample size basis
“There is no statistical rationale for the selected sample size of eight participants per cohort. The sample size was based on prior experience to ensure adequate initial assessment of the safety and tolerability of bepirovirsen while minimizing the number of patients unnecessarily exposed to the drug. The protocol included the ability to repeat a cohort if additional data at a specified cohort was warranted. No power calculation was performed.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Participants enrolled and the combination of cohorts 2 and 3
Description of analysis sets
Safety, full analysis, and per-protocol populations
“The safety population included all randomized patients who received one or more doses of bepirovirsen or placebo and was used for all safety analyses. The full analysis population (representing the practically feasible intent-to-treat population) included patients from the safety population with baseline and one or more post-baseline plasma HBV DNA concentrations. The per-protocol population included patients in the full analysis set who received at least five doses of bepirovirsen or placebo during the 4-week treatment period, had plasma HBV DNA concentration measured at day 29, and had no significant protocol deviations that would be expected to affect efficacy assessments. The full analysis and per protocol populations were used for efficacy endpoints.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Exploratory comparisons against pooled placebo
“There were no formal hypotheses; efficacy analyses for comparison between bepirovirsen and the pooled placebo group were performed in an exploratory manner.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The LOCF method was used to impute missing values. Comparison between bepirovirsen and a pooled placebo group was performed separately for each dose level using an analysis of covariance model with baseline as a covariate and treatment group as a factor.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Unplanned unblinded interim analyses
Results
Participant disposition
One withdrawal; all other participants completed
“One on-NA patient withdrew from the study on day 8, after two doses of bepirovirsen 300 mg, due to transient mild fevers after each dose that were considered treatment-related; all other patients completed the treatment and follow-up periods.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Baseline characteristics
Demographics and baseline characteristics (safety population)
Registry total age
Efficacy results
HBsAg reduction at day 29
“For treatment-naïve patients, the mean (s.d.) HBsAg reduction from baseline to day 29 was 0.50 (0.57) log10 IU ml−1 (P = 0.245 versus placebo) and 1.56 (1.38) log10 IU ml−1 (P = 0.001 versus placebo) in the bepirovirsen 150 mg and 300 mg arms, respectively (Table 3). For on-NA patients, the mean (s.d.) HBsAg reduction to day 29 was 1.99 (1.80) log10 IU ml−1 (Table 3). By contrast, no placebo-treated patient had a reduction in HBsAg of >0.07 log10 IU ml−1 by day 29. Four patients achieved transient HBsAg loss, defined as HBsAg level below the lower limit of quantitation (LLOQ: 0.05 IU ml−1), by day 29 (n = 3) or by day 36 (n = 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Significance in the on-NA cohort
“HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Depth and duration of HBsAg response with 300 mg in treatment-naive participants
“Six of 12 treatment-naïve patients receiving bepirovirsen 300 mg had HBsAg reduction ≥1.0 log10 IU ml−1 at day 29 (an additional patient had 0.98 log10-transformed reduction) (Fig. 1a). Three of these six patients experienced a reduction of ≥3.0 log10 and two achieved HBsAg loss.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
HBsAg response in the on-NA cohort
“Three of four on-NA patients completing bepirovirsen 300 mg dosing had a HBsAg reduction ≥3.0 log10 at day 29; of these three patients, one reached HBsAg levels below LLOQ on day 29 and another on day 36, whereas the third patient did not reach HBsAg levels below LLOQ.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The fourth patient had no decrease in HBsAg.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Change in HBsAg at week 31 in the registry results
| Measure | Cohort 1, 150 mg | Cohorts 2 and 3, 300 mg | Cohorts 1 to 3, placebo | Cohort 4, 300 mg | Cohort 4, placebo |
|---|---|---|---|---|---|
| Mean (SD) change, log10 IU/ml | “-0.523(0.9299)” | “-0.547(0.6109)” | “0.059(0.3859)” | “-1.519(1.4821)” | “-0.043(0.0178)” |
HBV DNA reduction at day 29 in treatment-naive participants
“The mean (s.d.) HBV DNA reduction from baseline to day 29 was 0.38 (0.42) log10 IU ml−1 (P = 0.116 versus placebo) and 1.66 (1.48) log10 IU ml−1 (P < 0.001 versus placebo) in the bepirovirsen 150 mg and 300 mg arms, respectively (Table 3).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Response by HBeAg status
“All four patients who reached undetectable HBsAg levels were HBeAg negative.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“In the 13 patients who were HBeAg-positive at baseline, minimal reductions in serum HBeAg concentration (IU ml−1) were observed from baseline to day 29 and to week 31 (Supplementary Table 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Transient anti-HBs positivity
“Transient treatment-emergent positivity for anti-HBs antibody, based on a qualitative test performed with the cut-off of ≥11.5 mIU ml−1, was observed for one of six and five of twelve treatment-naïve patients who received bepirovirsen 150 mg and 300 mg, respectively, and for one of five on-NA patients who received bepirovirsen 300 mg.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Health-related quality of life and patient-reported outcomes
No evidence found.
Safety results
Treatment-emergent adverse events
“Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Selected treatment-emergent adverse events (safety population)
Severity and the single serious adverse event
“TEAEs were mostly mild (division of acquired immune deficiency syndrome (DAIDS) grade 1: 52 of 69 events); the remainder were moderate (DAIDS grade 2: 16 of 69 events), except for one treatment-naïve patient in the bepirovirsen 300 mg treatment group who experienced a serious adverse event (DAIDS grade 4) of alanine aminotransferase (ALT) increase (described in the ‘ALT increase’ section).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
ALT flares
“Of the 18 treatment-naïve patients administered bepirovirsen, eight experienced an ALT flare: two patients in the bepirovirsen 150 mg arm and six in the bepirovirsen 300 mg arm.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“In the on-NA group, all patients had a normal ALT level at baseline; however, three of five patients receiving bepirovirsen 300 mg experienced an ALT flare. All ALT flares were transient and self-resolved.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“There were no concurrent changes in bilirubin (total and direct) for any patient.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Highest ALT value
“The highest ALT concentration observed was 781 U l−1 (23.7× ULN; ~26-fold change from baseline), which was recorded as a serious adverse event 15 d after the last dose of bepirovirsen 300 mg (week 6) in a treatment-naïve patient (Fig. 3a and Supplementary Fig. 8a).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“ALT and AST levels decreased substantially within 2 weeks and returned to baseline by week 17. The patient was asymptomatic throughout.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
C-reactive protein, coagulation, and complement
“An increase in C-reactive protein (CRP) levels following the first dose of bepirovirsen was observed in patients with CHB.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The magnitudes of these prolongations were not clinically relevant, with a maximum observed value of 43.9 s (~1.21× upper limit of normal (ULN); ULN = 36.5 s) in two participants in the bepirovirsen 300 mg treatment group.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“There were no observations of complement activation related to bepirovirsen dosing and no clinically significant findings in other safety assessments (for example, electrocardiogram, physical examination, concomitant medication usage).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registry serious adverse events and mortality
| Event, affected / at risk (%) | Cohort 1, 150 mg | Cohorts 2 and 3, 300 mg | Cohorts 1 to 3, placebo | Cohort 4, 300 mg | Cohort 4, placebo |
|---|---|---|---|---|---|
| All-cause mortality | “0/6 (0.00%)” | “0/12 (0.00%)” | “0/6 (0.00%)” | “0/5 (0.00%)” | “0/2 (0.00%)” |
| Serious adverse events, total | “0/6 (0.00%)” | “1/12 (8.33%)” | “0/6 (0.00%)” | “0/5 (0.00%)” | “0/2 (0.00%)” |
| Other adverse events (≥5%), total | “5/6 (83.33%)” | “6/12 (50.00%)” | “2/6 (33.33%)” | “3/5 (60.00%)” | “0/2 (0.00%)” |
Study limitations
Summary: study limitations
The trial randomized 31 participants: 24 treatment-naive participants in dose-escalation cohorts (6 to placebo, 6 to 150 mg, and 12 to 300 mg) and 7 participants receiving NA therapy in an exploratory cohort added by protocol amendment (2 to placebo and 5 to 300 mg). The sample size had no statistical rationale, no power calculation was performed, and efficacy comparisons with pooled placebo were exploratory and prespecified with no adjustment for multiple comparisons. Bepirovirsen was given for 4 weeks (six doses), and the approved label sets a maximum recommended treatment duration of 24 weeks. HBsAg loss occurred in 4 participants by day 29 or day 36, the registry results report 0% HBsAg loss at week 31 in every group, and the study did not include liver biopsies. All participants were Asian adults enrolled in Hong Kong and the Republic of Korea, Ionis sponsored the trial with support from GSK, and several authors were employees and shareholders of Ionis or GSK.
Limitations stated by the authors
“The limitations of this study include small patient numbers and the short duration of bepirovirsen treatment, which preclude a conclusion of whether bepirovirsen can achieve functional cure.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Furthermore, the study did not provide insight into effects in the liver due to the absence of liver biopsies.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Small sample in the on-NA cohort
“However, the absolute mean change from baseline in patients treated with bepirovirsen 300 mg was higher in the NA-treated group than in the treatment-naïve group, indicating that the lack of statistical significance may be due to the small sample size.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Small safety database and exclusion of cirrhosis
“However, given the small safety database, further characterization of ALT flares is warranted in future studies to further evaluate this hypothesis and rule out the possibility of drug-induced liver injury. Future studies should also consider the potential for grade 4 ALT flares in patients with cirrhosis, who were excluded in this study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Sponsor roles and author employment
“Ionis Pharmaceuticals, Inc. were involved in the conceptualization, design, data collection, analysis, decision to publish, and preparation of the manuscript; GlaxoSmithKline were involved in the analysis, decision to publish, and preparation of the manuscript.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Y. Tami, C.F.B. and T.J.K. are employees and stock/shareholders of Ionis Pharmaceuticals Inc. S.Y., P.Y., J.C., F.C., R.E., M.P. and D.T. are employees and stock/shareholders of GlaxoSmithKline.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
B-Fine
Objective
Mechanistic rationale
Questions the mechanistic investigation addresses
Location and study date
Registry record: identifiers, dates, enrollment, and locations
| Field | Quoted record |
|---|---|
| Other study identifier | “212602” |
| Study start (actual) | “2020-10-06” |
| Primary completion (actual) | “2023-11-30” |
| Enrollment (actual) | “12” |
| Number of listed locations | “This study has 4 locations” |
| Results first posted | “2024-12-19” |
Countries of the listed sites
“Boston, Massachusetts, United States, 02114” (opens the source at this quote in a new tab)
“Toronto, Ontario, Canada, M5G 2C4” (opens the source at this quote in a new tab)
“Rotterdam, Netherlands, 3015 GD” (opens the source at this quote in a new tab)
“London, United Kingdom, E1 1BB” (opens the source at this quote in a new tab)
Regulatory identifiers and protocol approval date
Study design
Phase IIa, multicentre, open-label, single-arm design with repeat liver fine needle aspiration
Study duration and visit frequency
Registered design details
| Field | Quoted record |
|---|---|
| Allocation | “N/A” |
| Interventional model | “Single Group Assignment” |
| Model description | “A single arm, multi-center, open label exploratory study.” |
| Masking | “None (Open Label)” |
Eligibility criteria
Rationale for enrolling HBeAg-negative participants on NA therapy
Treatment
Bepirovirsen dose, loading doses, and duration
Study outcomes
Rationale for using HBsAg below the lower limit of quantitation by week 12 as the primary endpoint
Primary endpoint and estimation approach
HBsAg loss as the treatment endpoint in chronic hepatitis B
Rationale from the phase 2a study for a longer treatment duration
Secondary endpoints: sustained HBsAg response and sustained virologic response
Statistical analysis description
Number of participants (Planned and analyzed)
Bayesian operating characteristics for 20 participants
Conditions for increasing the sample size
Description of analysis sets
Protocol analysis sets
| Analysis set | Quoted description |
|---|---|
| Intent to Treat (ITT) | “All participants who received at least one dose of study treatment” |
| Pharmacokinetic (PK) | “All participants in the Safety population who received an active study treatment and had at least 1 non-missing PK assessment (Non-quantifiable [NQ] values will be considered as non-missing values)” |
| Pharmacodynamic (PD) | “All participants in the Safety population for whom a Pharmacodynamic sample was obtained and analyzed.” |
| Analysis set for primary estimand | “All Intent to Treat Participants including all observations on and off treatment.” |
Handling of intercurrent events and immunomodulator use
Primary analysis: point estimate with 95% credible interval
Results
Participant disposition
Registry participant flow
| Disposition | Bepirovirsen 300 mg |
|---|---|
| Started | “12” |
| Completed | “11” |
| Not completed | “1” |
| Reason not completed | “Withdrawal by Subject” |
Baseline characteristics
Sex and race reported only as a de-identified category
Efficacy results
Primary and sustained response endpoints
| Endpoint | Participants analyzed | Percentage of participants |
|---|---|---|
| HBsAg <LLOQ up to Week 12 (primary) | “12” | “25” |
| Sustained HBsAg response for 24 weeks after planned end of treatment | “12” | “8” |
| Sustained HBsAg response for 24 weeks after actual end of treatment | “12” | “8” |
| Sustained virologic response for 24 weeks after planned end of treatment | “12” | “8” |
| Sustained virologic response for 24 weeks after actual end of treatment | “12” | “8” |
Intrahepatic and peripheral immunophenotyping presented at AASLD 2025
Health-related quality of life and patient-reported outcomes
No evidence found.
Safety results
Mortality, serious adverse events, and other adverse events
| Event | Affected / at risk (%) |
|---|---|
| All-cause mortality | “0/12 (0.00%)” |
| Serious adverse events, total | “0/12 (0.00%)” |
| Other adverse events, total | “11/12 (91.67%)” |
| Injection site erythema | “7/12 (58.33%)” |
| Injection site pruritus | “4/12 (33.33%)” |
| Procedural pain | “3/12 (25.00%)” |
| Injection site pain | “2/12 (16.67%)” |
| Pyrexia | “2/12 (16.67%)” |
| Fatigue | “2/12 (16.67%)” |
| Headache | “2/12 (16.67%)” |
| Alanine aminotransferase increased | “1/12 (8.33%)” |
| Hypertransaminasaemia | “1/12 (8.33%)” |
| Platelet count decreased | “1/12 (8.33%)” |
| Creatinine renal clearance decreased | “1/12 (8.33%)” |
Study limitations
Summary: study limitations
B-Fine was an open-label study without a control group: all 12 enrolled participants received bepirovirsen 300 mg, against a planned enrollment of approximately 20, and 11 completed. Enrollment was restricted to HBeAg-negative participants on stable NA therapy in order to “enrich for potential responders”, and treatment lasted 12 weeks, while the approved label sets a maximum recommended treatment duration of 24 weeks. The protocol's operating criterion was at least 12 of 20 participants (60%) reaching HBsAg below the LLOQ by week 12; the registry reports 25% for the primary endpoint and 8% for sustained HBsAg response 24 weeks after treatment. Sex and race were reported only as a de-identified category, and the intrahepatic immunophenotyping results are described in the GSK AASLD 2025 release only by poster titles.
Exploratory design without hypothesis testing
B-United
Objective
Purpose of the sequential regimen stated by the sponsor
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
Trial start and status reported by the sponsor
Study design
Phase 2b, randomized, partially placebo-controlled, double-blind design
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” |
Eligibility criteria
Key inclusion criteria
Treatment
Treatment arms by baseline HBsAg level and DAP/TOM dose
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
Registered secondary outcomes: functional cure by baseline HBsAg level and comparison with placebo plus bepirovirsen
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
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.
B-Focus
Objective
Location and study date
Study dates and status in the registry record
| Field | Registry entry |
|---|---|
| Recruitment status | “Active, not recruiting” |
| Study start (actual) | “2024-09-17” |
| Primary completion (estimated) | “2027-04-22” |
| Study completion (estimated) | “2027-04-22” |
| First posted | “2024-07-11” |
| Last update posted | “2026-07-08” |
Number of study locations
Study design
Multicenter, randomized, double-blind, placebo-controlled design
Design details in the registry record
| Field | Registry entry |
|---|---|
| Allocation | “Randomized” |
| Interventional model | “Parallel Assignment” |
| Masking description | “This will be a double-blind study.” |
| Phase | “Phase 2” |
| Other study identifiers | “219231” |
| EU trial number | “2023-509588-25” |
Eligibility criteria
Key inclusion criteria
Key exclusion criteria
Treatment
Antiretroviral therapy continued in coinfected patients
Study outcomes
Rationale for using HBV virologic response 36 weeks after the end of treatment as the primary endpoint
Registered primary outcome: HBsAg not detected and HBV DNA below the LLOQ at week 60
Registered secondary outcome: response at the end of treatment
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
Statistical analysis description
Number of participants (Planned and analyzed)
Enrollment in the registry record
| Field | Registry entry |
|---|---|
| Enrollment (actual) | “153” |
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-Focus is ongoing, with 153 participants enrolled, primary completion estimated for April 2027, and no results posted on ClinicalTrials.gov, so no efficacy or safety data are available in HIV-1 and HBV coinfection, a population excluded from B-Well 1 and B-Well 2. Participants remain on tenofovir-containing antiretroviral therapy throughout, so the primary outcome measures HBsAg not detected and HBV DNA below the LLOQ 36 weeks after the end of study treatment without discontinuation of nucleos(t)ide analogue therapy, which differs from the off-all-treatment endpoint of the pivotal trials. The registry does not state the bepirovirsen dose or treatment duration.
Study 217023 bepirovirsen followed by targeted immunotherapy
Objective
Basis for combining HBsAg reduction with therapeutic immunization
“Therapeutic vaccines likely require combination therapy for success.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“For example, pretreatment with agents that reduce HBsAg before therapeutic immunization and/or concurrent treatment with checkpoint inhibitors or other immune-activating agents might improve efficacy.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Location and study date
Study dates and status in the registry record
| Field | Registry entry |
|---|---|
| Recruitment status | “Completed” |
| Study start (actual) | “2022-03-22” |
| Primary completion (actual) | “2025-08-05” |
| Study completion (actual) | “2025-08-05” |
| First posted | “2022-03-11” |
| Last update posted | “2025-12-30” |
Number of study locations
Study design
Phase 2, single-blinded, randomized, controlled design
Design details in the registry record
| Field | Registry entry |
|---|---|
| Allocation | “Randomized” |
| Interventional model | “Sequential Assignment” |
| Masking description | “Open-label for Treatment 1 and single-blinded for Treatment 2.” |
| Phase | “Phase 2” |
| Other study identifiers | “217023” |
| EudraCT number | “2021-003567-10” |
| EU trial number | “2024-512352-38-00” |
Eligibility criteria
Key inclusion criteria
Key exclusion criteria: cirrhosis definitions and laboratory thresholds
Treatment
Bepirovirsen (GSK3228836) dosing in treatment 1
Targeted immunotherapy (GSK3528869A) or control in treatment 2
Four treatment groups
Study outcomes
Rationale for using grade 3 adverse events, serious adverse events, and sustained virologic response as the primary endpoints
Registered primary safety outcomes
Registered primary efficacy outcome: sustained virologic response
Reactogenicity of the immunotherapy regimen given alone in an earlier trial
“Grade 3 solicited adverse events (AEs) (median duration: 2–3 days) were more frequent after co-administration (systemic: 59.3%; administration-site: 33.3%) than sequential administration (systemic: 10.3%; administration-site: 12.8%) of high-dose viral vectors and proteins. No vaccine-related or fatal serious AEs were reported. After 4 doses, no participant had HBsAg loss or ≥1-log decrease in qHBsAg (D337 vs. D1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Statistical analysis description
Number of participants (Planned and analyzed)
Enrollment in the registry record
| Field | Registry entry |
|---|---|
| Enrollment (actual) | “174” |
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
Study 217023 enrolled 174 participants and was completed in August 2025; the sponsor submitted results to ClinicalTrials.gov on 2026-08-04, but no results are posted and no publication was identified, so its safety and efficacy outcomes cannot be assessed. The bepirovirsen regimens in this study (12 or 24 weeks with loading doses on days 4 and 11) were followed by an investigational immunotherapy or a non-active control, and only the 24-week regimen corresponds to the approved treatment duration. The follow-up period was reduced from 2 years to at least 1 year after the last dose during the study, and the immunotherapy regimen given alone produced no HBsAg loss in an earlier trial.
Results submitted but not posted
| Field | Registry entry |
|---|---|
| Results submitted to ClinicalTrials.gov | “2026-08-04” |
ISIS 505358-CS1 first-in-human phase 1 study
Objective
Aim of the first-in-human study
“We also present data from the phase 1 first‐in‐human study for bepirovirsen (study 213725; ISIS 50538‐CS1), which evaluated the PK, safety, and tolerability of single and multiple doses of bepirovirsen in healthy volunteers.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Location and study date
Single center in Canada, November 2013 to August 2014
“This phase 1, blinded, randomized, placebo‐controlled, dose‐escalation study in healthy volunteers was conducted at a single center (INC Research, Toronto, Ontario, Canada). The first participant was enrolled on November 12, 2013, and the last participant visit was on August 25, 2014.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Sponsor and study identifiers, corrected funding statement
“In the article cited above, the authors have determined that an error was present in the Funding section. The corrected Funding section is shown below.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“This phase 1 first‐in‐human study was, at the time of the trial, fully sponsored and funded by Ionis Pharmaceuticals, Inc. (ISIS 50538‐CS1). The study has since been acquired by GSK (Study 213725).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Study design
Blinded, randomized, placebo-controlled single-dose escalation
“Four sequential 4‐participant single‐dose cohorts (n = 4 for each cohort, alternative to 4 and 4) were randomized to bepirovirsen or placebo in a 3:1 ratio. Placebo was 0.9% sterile sodium chloride provided by the study center. Single doses of bepirovirsen were administered at dose levels of 75 mg (cohort A), 150 mg (cohort B), 300 mg (cohort C), or 450 mg (cohort D). Participants were followed for 30 days after treatment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Multiple-dose cohorts and escalation rules
“Three sequential 4‐participant multiple‐dose cohorts were randomly assigned to bepirovirsen or placebo in a 3:1 ratio. Participants received 6 doses of 150 mg (cohort M1), 300 mg (cohort M2), or 450 mg (cohort M3) over 3 weeks (dosing on days 1, 4, 8, 11, 15, and 22) and were followed for 13 weeks after treatment.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Stopping criteria were based on changes in liver chemistry, renal function, or platelet count (Supplemental Methods).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Eligibility criteria
Healthy adults aged 18 to 65 years
“Participants were men or nonpregnant and nonlactating women, 18–65 years of age, with a body mass index (BMI) ≤32.0 kg/m2. Participants were required to be healthy with no clinically significant abnormalities in medical history or screening laboratory values and no active infection requiring systemic antiviral or antimicrobial therapy not completed before day 1.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Treatment
Subcutaneous administration and split injections at doses of 300 mg or more
“Bepirovirsen or placebo was administered by subcutaneous (SC) injection into the upper arm, thigh, or abdomen. For dose levels ≥300 mg (cohorts C, D, M2, and M3), the dose was split into 2 equal injections and administered at 2 separate anatomic sites.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Cumulative doses in the multiple-dose cohorts
Study outcomes
Rationale for using safety and tolerability as the primary endpoint
Primary and secondary end points
Dose selection from preclinical exposure
“The preclinical transgenic mouse model showed that the 90% effective dose for HBsAg reduction was ≈20 mg/kg, which corresponds to a plasma PK exposure equivalent dose of 280 mg (4 mg/kg) of bepirovirsen in humans.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Statistical analysis description
Number of participants (Planned and analyzed)
Participants screened and randomized
Sample size basis
“The sample size was based on prior experience with other antisense oligonucleotides to ensure an adequate initial assessment of safety, tolerability, and PK while minimizing the number of participants exposed to bepirovirsen.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Description of analysis sets
Safety and PK populations, pooled placebo groups
“As there was only 1 placebo‐treated participant within each cohort, the placebo participants were pooled and analyzed as separate single‐dose and multiple‐dose placebo groups. The safety population included all participants who were randomized and received at least 1 dose of bepirovirsen; this population was used for all demographic, disposition, and safety analyses. The PK population included all participants who were randomized, received at least 1 dose of bepirovirsen and had any postdose plasma PK data.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Noncompartmental PK analysis and excluded samples
“Noncompartmental plasma PK analysis of bepirovirsen was carried out on each individual participant's data set, where full PK concentration‐time profiles were analyzed using WinNonLin Professional version 5.3 or higher (Pharsight Corp., Mountain View, California). Plasma concentrations in 2 samples, 1 from cohort C and 1 from cohort M3, were considered as outliers (0 or near 0 concentrations partway through the plasma concentration–time curve) and excluded from analyses.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Results
Participant disposition
Baseline characteristics
Sex, age, body mass index, and weight
“Baseline demographics and clinical characteristics were balanced across cohorts (Table S2). Over the full study population, there were 22 male and 6 female participants. In the single‐dose cohorts, the mean (standard deviation) age was 47.9 (11.7) years, BMI was 26.0 (2.4) kg/m2, and weight was 80.1 (11.2) kg at baseline. In the multiple‐dose cohorts, the mean (standard deviation) age was 51.1 (9.8) years, BMI was 27.1 (2.3), and weight was 80.2 (10.4) kg at baseline.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Efficacy results
Plasma PK parameters by cohort (arithmetic mean, SD; tmax median, range; n = 3 per cohort)
Absorption, dose proportionality, and accumulation
“Following a single SC injection of bepirovirsen, Cmax and total exposure, expressed as the AUC, increased with increasing dose (Table 1) and appeared to be dose proportional between 150 mg and 450 mg but were lower than dose proportional between 75 mg and 150 mg (Table 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Following the final dose on study day 22, the mean terminal plasma elimination half‐life was 22.4 to 24.2 days across cohorts. Cmin concentrations of bepirovirsen measured on study day 22 were similar to those on day 29, suggesting near steady‐state plasma levels had been achieved by day 22 as a result of the loading dose schedule included in weeks 1 and 2.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Urinary excretion of full-length bepirovirsen
Health-related quality of life and patient-reported outcomes
Not applicable.
Safety results
Treatment-emergent adverse events
“A total of 197 treatment‐emergent AEs were reported across all dose cohorts; the treatment‐emergent AE profile was similar between single‐ and multiple‐dose cohorts. There were no serious treatment‐emergent AEs, no treatment‐emergent AEs leading to discontinuation of the study or treatment, and no deaths.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The majority of treatment‐emergent AEs (128/197; 65%) were injection‐site reactions.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
C-reactive protein increases
“Six (50%) bepirovirsen‐treated participants in the single‐dose cohorts and 9 (100%) in the multiple‐dose cohorts had transient increases in C‐reactive protein (CRP) (single‐dose, Figure S11A; multiple‐dose, Figure 3A–D).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Peak CRP levels ranged from 4.2 to 53.3 mg/L; those with peak CRP levels >10 mg/L (n = 5 for single‐dose; n = 6 for multiple‐dose) were reported as treatment‐emergent AEs.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
ALT increases and platelet counts
“Five of 21 participants dosed with bepirovirsen had ALT increases to levels greater than the upper limit of normal (ULN; 41 U/L) (single‐dose, Figure S11B; multiple‐dose, Figure 3E–H). For all but 1 of these participants (in the 300‐mg multiple‐dose group) the maximum ALT levels ranged from 43 to 58 U/L (1.03–1.41 × ULN). The participant in the 300‐mg multiple‐dose cohort had 2 ALT increases that reached 2.6 × ULN, which were reported as a mild treatment‐emergent AE with a possible relationship to bepirovirsen.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“No significant dose effect was observed on platelet count in either single‐ or multiple‐dose cohorts.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Study limitations
Summary: study limitations
The first-in-human study enrolled 28 healthy volunteers at a single center in Canada, with 3 participants per active cohort and pooled placebo groups, so PK parameters rest on 3 values per dose and no participant had chronic HBV infection. Of 96 volunteers screened, 28 were randomized. The multiple-dose cohorts received 6 doses over 3 weeks, shorter than the approved 24-week course, and a 2025 correction to the funding section states that the study was “fully sponsored and funded by Ionis Pharmaceuticals, Inc.” at the time of the trial.
B-Assured hepatic impairment study
Objective
Location and study date
Two United States centers, September 2021 to May 2022
Study dates and status in the registry record
| Field | Registry entry |
|---|---|
| Recruitment status | “Completed” |
| Study start (actual) | “2021-09-07” |
| Primary completion (actual) | “2022-05-12” |
| Study completion (actual) | “2022-05-12” |
| Other study identifiers | “205871” |
| Last update posted | “2022-09-27” |
Study design
Two-part design with an interim decision rule
Eligibility criteria
Inclusion criteria and Child-Pugh classification
Treatment
Single 300 mg subcutaneous dose
Study outcomes
Rationale for using plasma AUC and cmax as the primary endpoints
Basis for the 0.5 to 1.5 geometric mean ratio thresholds
Need for a hepatic impairment study in the target population
Statistical analysis description
Number of participants (Planned and analyzed)
Description of analysis sets
Noncompartmental analysis and mixed effects model
Results
Participant disposition
Screen failures and completion of part 1
Baseline characteristics
Demographics by group
| Characteristic | Moderate hepatic impairment (N = 12) | Matched healthy controls (N = 12) |
|---|---|---|
| Age (years), mean (SD) | “59.9 (7.1)” | “60.9 (8.5)” |
| Female, n (%) | “5 (42)” | “5 (42)” |
| Weight (kg), mean (SD) | “88.6 (14.1)” | “84.9 (8.3)” |
| Hispanic or Latino, n (%) | “7 (58)” | “5 (42)” |
Efficacy results
Geometric mean ratios, moderate hepatic impairment versus matched healthy controls
Plasma PK parameters by group (geometric mean)
Hepatic impairment statement in the prescribing information
Health-related quality of life and patient-reported outcomes
Not applicable.
Safety results
Adverse events and adverse events of special interest
Study limitations
Summary: study limitations
B-Assured dosed 24 participants (12 with moderate hepatic impairment and 12 matched healthy controls) with a single 300 mg dose, and no participant had chronic HBV infection; the 12 participants with impairment had alcohol-related, hepatitis C, or nonalcoholic fatty liver disease cirrhosis. Part 2 in mild impairment was omitted, and the Part 1 findings were to be applied to participants with mild impairment. Unbound bepirovirsen was not measured. The prescribing information contraindicates bepirovirsen in chronic hepatitis B patients with cirrhosis of any Child-Pugh class.
Limitations stated by the investigators
B-Kind renal impairment study
Objective
Location and study date
Study dates and status in the registry record
| Field | Registry entry |
|---|---|
| Recruitment status | “Active, not recruiting” |
| Study start (actual) | “2025-09-26” |
| Primary completion (actual) | “2026-03-03” |
| Study completion (estimated) | “2026-08-18” |
| First posted | “2025-09-11” |
| Last update posted | “2026-05-22” |
Study locations in the registry record
“This study has 3 locations” (opens the source at this quote in a new tab)
“Orlando, Florida, United States, 32809” (opens the source at this quote in a new tab)
“Tampa, Florida, United States, 33603” (opens the source at this quote in a new tab)
“San Antonio, Texas, United States, 78215” (opens the source at this quote in a new tab)
Study design
Phase 1, open-label, single-dose, parallel-group design
Design details in the registry record
| Field | Registry entry |
|---|---|
| Allocation | “Non-Randomized” |
| Interventional model | “Parallel Assignment” |
| Masking description | “This is an open-label study.” |
| Phase | “Phase 1” |
| Other study identifiers | “205872” |
Eligibility criteria
Renal function groups
Other inclusion and exclusion criteria
Treatment
Single dose of bepirovirsen in each group
Study outcomes
Rationale for using plasma AUC and cmax as the primary endpoints
Registered primary and secondary outcomes
Renal impairment data gap in the prescribing information
Statistical analysis description
Number of participants (Planned and analyzed)
Enrollment in the registry record
| Field | Registry entry |
|---|---|
| Enrollment (actual) | “32” |
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
Not applicable.
Safety results
No evidence found.
Study limitations
Summary: study limitations
B-Kind reached primary completion on 2026-03-03 with 32 participants enrolled, but no results are posted on ClinicalTrials.gov and no publication was identified, and the prescribing information states that data are insufficient in moderate or severe renal impairment. The 32 participants are divided among three groups, each participant receives a single dose, and the registry excludes participants with a positive hepatitis B test, dialysis, or renal transplantation.
Study 219239 relative bioavailability of vial and prefilled syringe
Objective
Aim stated in the publication
“The current study was designed to evaluate the relative bioavailability of bepirovirsen when delivered via SC injection from a vial (HCP‐administered) or by a PFS SSD (HCP‐ or self‐administered) in healthy adult participants. Safety and tolerability were assessed as a secondary objective.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Location and study date
Study dates and status in the registry record
| Field | Registry entry |
|---|---|
| Recruitment status | “Completed” |
| Study start (actual) | “2023-10-04” |
| Primary completion (actual) | “2024-05-03” |
| Study completion (actual) | “2024-05-03” |
| Results first posted | “2025-07-18” |
| Other study identifiers | “219239” |
Study design
Randomized, open-label, parallel-group design with stratification
“This was a Phase 1, open‐label, randomized, parallel‐group study (219239, NCT06058390). Participants were randomized 3:3:2:2 to receive a single dose of bepirovirsen 300 mg either administered by a HCP from a vial (Group 1), administered by a HCP using the PFS SSD (Group 2), self‐administered using the PFS SSD with training from a HCP (Group 3), or self‐administered using the PFS SSD without training from a HCP (Group 4) (Figure 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The randomization was stratified by body weight (50‐<70 kg, 70‐<80 kg, and ≥80 kg). The site of injection was randomized in a 1:1:1 ratio to the upper arm, abdomen, or thigh in Groups 1 and 2, and in a 1:1 ratio to abdomen or thigh in Groups 3 and 4.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Eligibility criteria
Inclusion and exclusion criteria in the publication
“Healthy male and female participants, aged between 18 and 55 years, were enrolled from 2 centers in the United States. Participants were required to have body weight ≥50 kg and body mass index (BMI) within 19‐29.9 kg/m2.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Participants were excluded if they had: a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; or any malignancy within the past 5 years; platelets <140×109/L; alanine aminotransferase (ALT) >1.5× upper limit of normal (ULN), or total bilirubin >1.5×ULN; a current or chronic history of liver disease or known hepatic or biliary abnormalities; or prior treatment with any oligonucleotide or siRNA within 12 months before dosing.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Treatment
Single 300 mg dose given as two 150 mg injections
“All participants received a single dose of bepirovirsen 300 mg either by vial or PFS SSD, given as two 150 mg SC injections that were given as close together in time as possible (within 5 min) and spaced at least 5 cm apart.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Prefilled syringe with safety syringe device
“The bepirovirsen PFS SSD consisted of a sterile liquid drug product in a single‐use clear glass PFS assembled into an SSD that delivered 1 mL of 150 mg/mL bepirovirsen for SC administration.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The formulation of bepirovirsen is identical between the vial and the PFS SSD.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Study outcomes
Rationale for using relative bioavailability (Plasma cmax and AUC) as the primary endpoint
Primary and secondary endpoints and the bioequivalence criterion
“The primary endpoint was to estimate the relative bioavailability of a single dose of bepirovirsen delivered by SC injection by a HCP in healthy participants using a vial versus PFS SSD.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Bepirovirsen exposure was considered to be bioequivalent if the 90% CIs for the GMRs of both Cmax and AUC(0‐inf) fell within the standard bioequivalence reference range of 0.80 to 1.25.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Purpose of the bioavailability comparison
Statistical analysis description
Number of participants (Planned and analyzed)
Participants screened, enrolled, and analyzed
“A total of 359 participants were screened and 160 participants enrolled in the study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The latter participant was not included in the analysis, leading to a total study analysis population of 159 participants (Group 1, n = 46; Group 2, n = 49; Group 3, n = 32; Group 4, n = 32).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“A total of 153 of the 159 study analysis participants were included in the PK summaries and statistical comparisons of the PK data for the primary and secondary endpoint analyses.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Description of analysis sets
Analysis sets in the registry results
Statistical model for relative bioavailability
“For each of the primary and secondary endpoints, data were analyzed using separate linear fixed effects models with randomized group (i.e. Group 1 versus Group 2 for the primary analysis; Group 2 versus Group 3, and Group 2 versus Group 4 for the secondary analyses) and injection site (arm, abdomen, or thigh for Groups 1 and 2, and abdomen or thigh for Groups 3 and 4) included as categorical covariates, and natural logarithm transformed baseline weight as a continuous covariate.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Results
Participant disposition
Withdrawals and incomplete doses
“In total, 5 participants across Groups 3 and 4 withdrew from the study, of whom 1 participant (Group 4) was withdrawn due to physician decision (based on failure to cooperate and complete outpatient visits), 3 participants (2 in Group 3 and 1 in Group 4) were lost to follow‐up, and 1 participant (Group 4) did not remove the cap from the PFS SSD during dosing and did not receive any study intervention.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“There were 6 participants (3 in Group 3 and 3 in Group 4) who each received an incomplete dose (of either the first or second dose or both) of study intervention due to incorrect use of the PFS and were excluded from the PK analyses (Table S3).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Baseline characteristics
Demographics of the analysis population
“In the overall study population, 52% of participants were female, the mean (SD) age was 36.5 (9.35) years, and the mean (SD) BMI was 25.68 (2.746) kg/m2. The majority of participants were of White (48%) or Black/African American (35%) race and were not of Hispanic/Latino ethnicity (67%). Most of the participants were in the 50 to <70 kg (39%) and 70 to <80 kg (36%) weight categories, with similar distribution between weight categories across all 4 treatment groups.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Efficacy results
Primary endpoint: vial versus PFS SSD given by a healthcare professional
“Analysis of the primary endpoint demonstrated the bioequivalence of bepirovirsen exposure from a vial versus PFS SSD when HCP‐administered, as the GMR (90% CI) was 1.02 (0.91, 1.14) for Cmax and 1.05 (0.96, 1.15) for AUC(0‐inf) (Table 3).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Secondary endpoints: self-administration with and without training
“The GMR (90% CI) with participant training (Group 2 versus Group 3) was 1.02 (0.88, 1.18) for Cmax and 0.98 (0.88, 1.09) for AUC(0‐inf), and without participant training (Group 2 versus Group 4) was 0.99 (0.87, 1.13) for Cmax and 0.97 (0.87, 1.08) for AUC(0‐inf).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Plasma PK parameters by group (geometric mean, % CV)
| Parameter | Vial by HCP (N = 46) | PFS SSD by HCP (N = 49) | PFS SSD self-administered with training (N = 29) | PFS SSD self-administered without training (N = 29) |
|---|---|---|---|---|
| Cmax (ng/mL) | “9873.38 (40.96)”View highlighted excerpt for this quote | “10,242.48 (39.54)”View highlighted excerpt for this quote | “10,391.83 (42.70)”View highlighted excerpt for this quote | “9516.35 (47.41)”View highlighted excerpt for this quote |
| AUC(0‐inf) (ng·h/mL) | “111,843.70 (32.93)”View highlighted excerpt for this quote | “119,271.61 (29.70)”View highlighted excerpt for this quote | “119,080.46 (26.28)”View highlighted excerpt for this quote | “112,338.58 (35.01)”View highlighted excerpt for this quote |
Effect of body weight and injection site
“Between the 50‐<70kg and ≥80kg groups, there was a decrease of 24%‐47% in geometric mean Cmax and a decrease of 19%‐43% in geometric mean AUC(0‐inf).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Across all treatment groups the geometric mean Cmax of bepirovirsen tended to be lower when administered in the thigh compared with the other injection sites.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registry results: 90% confidence intervals for the primary comparison
Health-related quality of life and patient-reported outcomes
Not applicable.
Safety results
Overall adverse events
“A total of 94% (150/159) of participants reported AEs, with similar proportions of participants reporting AEs across all treatment groups (88‐100%; Table 5 and Table S4). Most AEs were considered related to study drug by the investigator (148/159 participants [93%]; Table S5). There were no serious or fatal AEs. Most AEs were Grade 1/2 in severity; <10% of participants reported Grade 3 AEs, and no Grade 4, Grade 5, or unknown Grade AEs were reported.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Adverse events reported in at least 3% of participants overall
Adverse events of special interest: injection site reactions, thrombocytopenia, and ALT increases
“The proportion of participants experiencing injection site reactions was higher when PFS SSD was self‐administered (Group 3: 32/32 [100%], Group 4: 30/32 [94%]) compared with HCP administration (Group 2: 43/49 [88%]).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“AESIs related to thrombocytopenia were reported by 18% (29/159) of participants with no clear difference between treatment groups” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Both ALT increases were <5× ULN. One participant in the self‐administered PFS SSD without training group reported a Grade 3 platelet decline to <100×109/L. This occurred 65 days after study‐dose administration, the participant was asymptomatic and had no clinical bleeding.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Deaths, serious adverse events, and thrombocytopenia in the registry results
| Event | Vial by HCP | PFS SSD by HCP | PFS SSD self-administered after training | PFS SSD self-administered without training |
|---|---|---|---|---|
| All-cause mortality | “0/46 (0.00%)” | “0/49 (0.00%)” | “0/32 (0.00%)” | “0/32 (0.00%)” |
| Serious adverse events | “0/46 (0.00%)” | “0/49 (0.00%)” | “0/32 (0.00%)” | “0/32 (0.00%)” |
| Thrombocytopenia | “1/46 (2.17%)” | “0/49 (0.00%)” | “0/32 (0.00%)” | “2/32 (6.25%)” |
Study limitations
Summary: study limitations
Study 219239 compared a single 300 mg dose in 159 healthy participants aged 18 to 55 years, so it provides no information on repeated dosing over the 24-week course or on device use by patients with chronic hepatitis B. Six participants in the self-administration groups (3 in Group 3 and 3 in Group 4, each of 32 participants) received an incomplete dose because of incorrect use of the prefilled syringe and were excluded from the PK analyses, and injection site reactions occurred in 100% and 94% of the self-administration groups compared with 88% with healthcare professional administration. Exposure was lower in the thigh and decreased with increasing body weight, and the authors state that it is unclear whether the injection-site difference is real or due to variability.
Limitations stated by the investigators
“However, the use of healthy participants may also be considered a limitation because this is not the intended population for bepirovirsen; this is a common approach for relative bioavailability studies, owing to the difficulty of enrolling patients in a single‐dose study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“It is unclear from the data whether the difference in exposure by injection site is real or due to variability.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“While 6 participants received an incomplete dose of bepirovirsen, owing to incorrect use of the PFS (4 of them injected approximately 75% to 95% of the dose), device usability was evaluated in separate formative and summative human factors studies, and the device and instructions for use were successfully validated for self‐administration (unpublished data).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Study 205873 thorough QT study
Objective
Purpose stated in the protocol
Location and study date
Study dates and status in the registry record
| Field | Registry entry |
|---|---|
| Recruitment status | “Completed” |
| Study start (actual) | “2024-07-18” |
| Primary completion (actual) | “2025-04-28” |
| Study completion (actual) | “2025-04-28” |
| Results first posted | “2026-07-10” |
| Other study identifiers | “205873” |
Study design
Randomized, double-blind, placebo-controlled, parallel-group design
Planned 1:1 randomization and dose reduction under protocol amendment 2
Supratherapeutic doses stated in the prescribing information
Eligibility criteria
Key inclusion criteria
Key exclusion criteria
Treatment
Arms in the registry record
| Arm | Registry entry |
|---|---|
| Bepirovirsen, four injections | “Participant received four subcutaneous (SC) injections of Bepirovirsen dose level 1 on Day 1.” |
| Placebo, four injections | “Participants received four matching placebo SC injections on Day 1.” |
| Bepirovirsen, three injections | “Participant received three SC injections of Bepirovirsen dose level 1 on Day 1.” |
| Placebo, three injections | “Participants received three matching placebo SC injections on Day 1.” |
Study outcomes
Rationale for using placebo-corrected change from baseline in QTcF as the primary endpoint
Registered primary outcome and concentration-QTc method
Regulatory basis in the ICH E14 guidance
Hypothesis threshold of 10 msec
Statistical analysis description
Number of participants (Planned and analyzed)
Planned sample size and power
Description of analysis sets
Analysis sets defined in the protocol
Population for the primary analysis in the registry results
Results
Participant disposition
Baseline characteristics
Age in the registry results
| Characteristic | Bepirovirsen, four injections | Placebo, four injections | Bepirovirsen, three injections | Placebo, three injections | Total |
|---|---|---|---|---|---|
| Overall number of baseline participants | “5” | “5” | “18” | “18” | “46” |
| Age (years), mean (SD) | “31.4(11.24)” | “33.2(4.02)” | “39.4(7.96)” | “38.6(10.29)” | “37.5(9.20)” |
Efficacy results
Primary outcome: placebo-corrected change from baseline in QTcF at Cmax
| Arm | Participants analyzed | Geometric mean (ms) | 90% CI (ms) |
|---|---|---|---|
| Bepirovirsen, four injections | “5” | “2.360” | “(-0.249 to 4.970)” |
| Bepirovirsen, three injections | “18” | “2.024” | “(-0.541 to 4.589)” |
Health-related quality of life and patient-reported outcomes
Not applicable.
Safety results
Deaths, serious adverse events, and other adverse events in the registry results
| Event | Bepirovirsen, four injections | Placebo, four injections | Bepirovirsen, three injections | Placebo, three injections |
|---|---|---|---|---|
| All-cause mortality | “0/5 (0.00%)” | “0/5 (0.00%)” | “0/18 (0.00%)” | “0/18 (0.00%)” |
| Any other (not serious) adverse event | “5/5 (100.00%)” | “1/5 (20.00%)” | “15/18 (83.33%)” | “2/18 (11.11%)” |
| Injection site erythema | “5/5 (100.00%)” | “0/5 (0.00%)” | “14/18 (77.78%)” | “0/18 (0.00%)” |
| Injection site swelling | “4/5 (80.00%)” | “0/5 (0.00%)” | “13/18 (72.22%)” | “0/18 (0.00%)” |
| Injection site pain | “3/5 (60.00%)” | “0/5 (0.00%)” | “9/18 (50.00%)” | “0/18 (0.00%)” |
| Headache | “3/5 (60.00%)” | “0/5 (0.00%)” | “5/18 (27.78%)” | “1/18 (5.56%)” |
| Nausea | “3/5 (60.00%)” | “0/5 (0.00%)” | “3/18 (16.67%)” | “0/18 (0.00%)” |
| Pyrexia | “0/5 (0.00%)” | “0/5 (0.00%)” | “4/18 (22.22%)” | “0/18 (0.00%)” |
Study limitations
Summary: study limitations
Study 205873 gave a single supratherapeutic dose of bepirovirsen to 5 participants by four injections and 18 by three injections, with 5 and 18 placebo recipients in the corresponding arms; the higher-dose arm was stopped after 2 participants had systemic tolerability issues, leaving 5 participants at that dose. The registry describes the dose only as “dose level 1”, and the prescribing information states the supratherapeutic doses as 450 and 600 mg. AUC extrapolated to infinity was not calculated because there were not enough data points for a terminal slope, and single-dose data in healthy volunteers do not describe QTc effects during the 24-week course in patients with chronic hepatitis B.