---
title: "Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Clinical evidence"
description: "Formulary evidence on Hibsago (bepirovirsen, GSK3228836) in Chronic hepatitis B virus infection in adults without cirrhosis: Clinical evidence. Covers B-Well 1, B-Well 2, B-Clear, B-Sure, B-Together, ISIS 505358-CS3 phase 2a study, and 9 further headings. 684 evidence topics quoted from 69 sources."
canonical: "https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/clinical-evidence"
published: "2026-10-21T22:39:04-04:00"
modified: "2026-10-22T19:07:03-04:00"
---

# Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Clinical evidence

<a id="clinical-evidence"></a>

## 3 Clinical Evidence

<a id="heading-3.1"></a>

### 3.1 Study Summaries

<a id="heading-3.1.1"></a>

#### 3.1.1 B-Well 1

<a id="heading-3.1.1.1"></a>

##### 3.1.1.1 Objective

<a id="topic-3.1.1.1-1"></a>

###### Purpose stated in the ClinicalTrials.gov brief summary

> “This study is intended to confirm the efficacy, safety, pharmacokinetic (PK) profile, and the durability of hepatitis B virus surface antigen (HBsAg) suppression observed with bepirovirsen for 24 weeks (with loading doses) as compared to the placebo arm.”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.1-2"></a>

###### Main objective in the EU Clinical Trials Information System record

> “To assess the treatment effect of 24 weeks bepirovirsen with loading doses to achieve functional cure in participants with chronic HBV infection on NA treatment with baseline HBsAg ≤3000 IU/mL”

Source: [EU Clinical Trials Information System 2023-504239-41-00](https://euclinicaltrials.eu/ctis-public/view/2023-504239-41-00)

<a id="topic-3.1.1.1-3"></a>

###### Main and secondary objectives in the EU Clinical Trials Register record

> “Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses in HBV DNA suppression off-treatment after a finite duration of therapy in participants with chronic HBV infection on NA treatment”
> “Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses in HBV DNA suppression after a finite duration of therapy in participants with chronic HBV infection on NA treatment”
> “Safety: To assess the safety and tolerability of bepirovirsen when dosed for 24 weeks duration with loading doses in participants with chronic HBV infection on NA treatment”

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="topic-3.1.1.1-4"></a>

###### Trial description in the company pipeline appendix

> “A multicentre, randomised, double blind trial to confirm the efficacy and safety of treatment with bepirovirsen in participants with chronic hepatitis B virus”

Source: [GSK FY2025 pipeline assets and clinical trials appendix (2026)](https://www.gsk.com/media/rs0mbgqw/fy-2025-pipeline-assets-and-clinical-trials-report.pdf)

<a id="topic-3.1.1.1-5"></a>

###### Aims of both B-Well trials stated by the company

> “They assessed the efficacy, safety, pharmacokinetic profile, and durability of functional cure in nucleos(t)ide analogue-treated adult participants with chronic hepatitis B and baseline surface antigen (HBsAg) ≤3000 IU/ml.”

Source: [GSK press release, Hibsago US approval (2026)](https://www.gsk.com/en-gb/media/press-releases/hibsago-bepirovirsen-approved-in-the-us-for-the-treatment-of-chronic-hepatitis-b-chb/)

<a id="heading-3.1.1.2"></a>

##### 3.1.1.2 Location and Study Date

<a id="topic-3.1.1.2-1"></a>

###### Study dates and status in the ClinicalTrials.gov record

> “Study Start (Actual) 2022-12-07”
> “Primary Completion (Actual) 2025-11-11”
> “Study Completion (Actual) 2026-04-15”
> “First Posted 2022-11-30”
> “Last Update Posted 2026-07-08”
> “Completed”
> “No Results Posted”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.2-2"></a>

###### Number of locations in the ClinicalTrials.gov record

> “This study has 177 locations”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.2-3"></a>

###### Study locations by country in the ClinicalTrials.gov record

| Country | Locations listed in the record |
| --- | --- |
| United States | “Chandler, Arizona, United States, 85224”; “Davis, California, United States, 95817”; “Los Angeles, California, United States, 90027”; “Palo Alto, California, United States, 94304”; “San Jose, California, United States, 95116”; “Littleton, Colorado, United States, 80120”; “Miami, Florida, United States, 33134”; “Iowa City, Iowa, United States, 52242”; “Baltimore, Maryland, United States, 21287”; “Detroit, Michigan, United States, 48377”; “Richmond, Virginia, United States, 23249”; “Richmond, Virginia, United States, 23298” |
| Argentina | “Buenos Aires, Argentina, 1061”; “Buenos Aires, Argentina, C1061AAS”; “Buenos Aires, Argentina, C1125ABE”; “Capital Federal, Argentina, C1181ACI”; “Derqui Pilar, Argentina, B1629AHJ”; “Rosario, Argentina, S2002KDT” |
| Brazil | “Aracaju, Brazil, 49060-010”; “Campinas, Brazil, 13034-685”; “Curitiba, Brazil, 80810-050”; “Manaus, Brazil, 69040-000”; “Porto Alegre, Brazil, 90035003”; “Santa Maria, Brazil, 97105-900”; “São Paulo, Brazil, 05403-000”; “São Paulo, Brazil, 08270-070”; “Vila Mariana, Brazil, 04121-000” |
| Bulgaria | “Sofia, Bulgaria, 1431”; “Sofia, Bulgaria, 1606”; “Sofia, Bulgaria”; “Veliko Tarnovo, Bulgaria, 5000” |
| Canada | “Vancouver, British Columbia, Canada, V6Z 2K5”; “Victoria, British Columbia, Canada, V8V 3M9”; “Ottawa, Ontario, Canada, K1H 8L6”; “Toronto, Ontario, Canada, M5G 2C4”; “Montreal, Quebec, Canada, H2X 0A9”; “Montreal, Quebec, Canada, H4A 3J1”; “Québec, Quebec, Canada, G1V 4G2”; “Saint-Jérôme, Quebec, Canada, J7Z 2V4” |
| China | “Beijing, China, 100015”; “Beijing, China, 100050”; “Beijing, China”; “Changchun, China, 130021”; “Chengdu, China”; “Chongqing, China, 400042”; “Fuzhou, China, 350025”; “Guangzhou, China, 510060”; “Guangzhou, China, 510515”; “Guangzhou, China, 510630”; “Hangzhou, China, 310003”; “Hangzhou, China, 310022”; “Kunming, China, 650021”; “Nanjing, China, 210008”; “Shanghai, China, 200025”; “Shanghai, China, 200040”; “Shanghai, China, 200083”; “Shenyang, China, 110022”; “Shenzhen, China, 518112”; “Ürümqi, China, 830054”; “Wuhan, China, 430022”; “Xi'an, China, 710061”; “Zhengzhou, China, 450000”; “Zhenjiang, China” |
| France | “Clermont-Ferrand, France, 63003”; “Clichy, France, 92118”; “Dijon, France, 21079”; “Lille, France, 59037”; “Pessac, France, 33604”; “Poitiers, France, 86021”; “Rennes, France, 35033”; “Strasbourg, France, 67091”; “Toulouse, France, 31059” |
| Germany | “Berlin, Germany, 10243”; “Berlin, Germany, 10439”; “Berlin, Germany, 10787”; “Berlin, Germany, 12163”; “Bochum, Germany, 44787”; “Cologne, Germany, 50668”; “Düsseldorf, Germany, 40225”; “München, Germany, 80336” |
| Greece | “Athens, Greece, 10676”; “Athens, Greece, 11527”; “Periohi Dragana Alexand, Greece, 68100”; “Rio Patras, Greece, 26504” |
| Hong Kong | “Kowloon, Hong Kong”; “Pokfulam, Hong Kong”; “Shatin, Hong Kong” |
| Hungary | “Budapest, Hungary, 1097”; “Eger, Hungary, 3300”; “Gyula, Hungary, 5700”; “Miskolc, Hungary, 3530” |
| India | “Belagavi, India, 590010”; “Chandigarh, India, 160012”; “Chennai, India, 600113”; “Coimbatore, India, 641005”; “Guhawati, India, 781006”; “Hyderabad, India, 500033”; “HyderabadTelangana, India, 500048”; “Jaipur, India, 302001”; “Ludhiana, India, 141001”; “Manipal, India, 576104”; “Mumbai, India, 400 008”; “Mumbai, India, 400012”; “Mumbai, India, 400026”; “Pune, India, 411001”; “Surat, India, 395002” |
| Italy | “Brescia, Italy, 25123”; “Foggia, Italy, 71100”; “Messina, Italy, 98124”; “Milan, Italy, 20122”; “Milan, Italy, 20162”; “Modena, Italy, 40126” |
| Japan | “Chiba, Japan, 272-8516”; “Ehime, Japan, 790-8524”; “Fukuoka, Japan, 820-8505”; “Fukuoka, Japan, 839-0863”; “Gifu, Japan, 500-8717”; “Gifu, Japan, 503-8502”; “Hiroshima, Japan, 734-8551”; “Hiroshima, Japan, 737-0023”; “Hokkaido, Japan, 053-8506”; “Hyōgo, Japan, 660-8550”; “Kumamoto, Japan, 862-8655”; “Miyagi, Japan, 980-8574”; “Tokyo, Japan, 113-8519”; “Tokyo, Japan, 173-8610”; “Tokyo, Japan, 180-8610” |
| Malaysia | “George Town, Malaysia”; “Johor Bahru, Malaysia, 80100”; “Kota Bharu Kelantan, Malaysia”; “Kota Kinabalu, Malaysia”; “Kuala Lumpur, Malaysia”; “Kuantan, Malaysia” |
| Mexico | “Guadalajara, Mexico, 44160”; “Oaxaca City, Mexico, 68000” |
| Panama | “Panama City, Panama, 07206” |
| Poland | “Bytom, Poland, 41-902”; “Krakow, Poland, 31-202”; “Łańcut, Poland, 37-100” |
| Romania | “Bucharest, Romania, 021105”; “Bucharest, Romania, 20125”; “Cluj-Napoca, Romania, 400162”; “Iași, Romania, 700116”; “Suceava, Romania, 720224”; “Timișoara, Romania, 300001” |
| Singapore | “Singapore, Singapore, 119074”; “Singapore, Singapore, 169608” |
| South Korea | “Ansan, South Korea, 15355”; “Busan, South Korea, 47392”; “Daegu, South Korea, 41944”; “Daegu, South Korea, 42601”; “Seoul, South Korea, 03080”; “Seoul, South Korea, 06351”; “Seoul, South Korea, 07061”; “Seoul, South Korea, 08308” |
| Spain | “Barcelona, Spain, 08035”; “Barcelona, Spain, 08036”; “León, Spain, 24080”; “Madrid, Spain, 28041”; “Málaga, Spain, 29010”; “Salamanca, Spain, 37007”; “Santander, Spain, 39008”; “Valencia, Spain, 46014”; “Valladolid, Spain, 47003”; “Vigo, Spain, 36002” |
| Taiwan | “Kaohsiung City, Taiwan, 807”; “Kaohsiung City, Taiwan, 833”; “Taichung, Taiwan, 40705”; “Taipei, Taiwan, 104”; “Tau-Yuan, Taiwan, 333” |
| Thailand | “Bangkok, Thailand, 10330” |
| Turkey (Türkiye) | “Ankara, Turkey (Türkiye), 06230” |
| United Kingdom | “Birmingham, United Kingdom, B15 2TH”; “Edinburgh, United Kingdom, EH4 2XU”; “Leeds West Yorkshire, United Kingdom, LS9 7TF”; “London, United Kingdom, SE5 9RS”; “London, United Kingdom, SW17 0QT” |

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.2-4"></a>

###### EU and EEA member states, trial start, and end of trial in the EU Clinical Trials Information System record

> “Locations Bulgaria, Germany, Spain, France, Greece, Hungary, Poland, Romania, Italy”
> “Start of trial 09/01/2023”
> “End of trial 17/03/2026”
> “Global end of trial 15/04/2026”
> “Estimated recruitment start date in EU/EEA: 13/01/2023”

Source: [EU Clinical Trials Information System 2023-504239-41-00](https://euclinicaltrials.eu/ctis-public/view/2023-504239-41-00)

<a id="topic-3.1.1.2-5"></a>

###### Planned sites in the European Economic Area and regulatory and ethics decisions in the EU Clinical Trials Register record

> “Number of sites anticipated in the EEA 50”
> “Trial being conducted both within and outside the EEA Yes”
> “Date of Competent Authority Decision 2023-01-26”
> “Date of Ethics Committee Opinion 2022-12-16”

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="topic-3.1.1.2-6"></a>

###### Regions with planned trial sites in the EU Clinical Trials Register record

> “Argentina Panama Singapore Hong Kong Taiwan Brazil Canada China India Japan Korea, Republic of Mexico Thailand Turkey United Kingdom United States Bulgaria France Germany Greece Hungary Italy Poland Romania Spain”

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="topic-3.1.1.2-7"></a>

###### Countries in both B-Well trials stated by the company

> “B-Well 1 and B-Well 2 trials are global multi-centre, randomised, double-blind, placebo-controlled trials conducted in 29 countries.”

Source: [GSK press release, B-Well topline (2026)](https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-results-from-b-well-1-and-b-well-2-phase-iii-trials-for-bepirovirsen-a-potential-first-in-class-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.1.2-8"></a>

###### Trial start in the company pipeline appendix

> “Trial start: Q4 2022”

Source: [GSK FY2025 pipeline assets and clinical trials appendix (2026)](https://www.gsk.com/media/rs0mbgqw/fy-2025-pipeline-assets-and-clinical-trials-report.pdf)

<a id="topic-3.1.1.2-9"></a>

###### Initiation of the two phase 3 studies announced by the licensor

> “CARLSBAD, Calif., Feb. 1, 2023 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced that GSK has initiated two randomized, double-blind, placebo-controlled Phase 3 studies evaluating the safety and efficacy of bepirovirsen (formerly IONIS-HBVRx), an investigational antisense medicine for the treatment of patients with chronic hepatitis B infection (CHB).”

Source: [Ionis press release, phase 3 start (2023)](https://ir.ionis.com/node/29351)

<a id="heading-3.1.1.3"></a>

##### 3.1.1.3 Study Design

<a id="topic-3.1.1.3-1"></a>

###### Official title in the ClinicalTrials.gov record

> “Phase 3 Multicenter, Randomized, Double-Blind, Study to Assess the Efficacy and Safety of Treatment With Bepirovirsen in Nucleos(t)Ide Analogue-treated Participants With Chronic Hepatitis B Virus (B-Well 1)”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.3-2"></a>

###### 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.” |

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.3-3"></a>

###### Four study stages, stratification, and total duration in the ClinicalTrials.gov record

> “This study will have 4 stages: a) Double-blind treatment (bepirovirsen or placebo) for 24 weeks. b) Nucleos(t)ide analogue (NA) treatment for 24 weeks. c) NA cessation stage OR Continue NA for 24 weeks. d) Durability of response and follow up for further 24 weeks for participants who stopped NA treatment at Week 48.”
> “The arms will be stratified based on HBsAg level (HBsAg greater than or equal to [≥] 100 international unit per milliliter [IU/mL] to less than or equal [≤]1000 IU/mL or greater than [>] 1000 IU/mL to ≤3000 IU/mL) at screening.”
> “The total duration of the study, including screening (up to 60 days), the double-blind treatment stage (24 weeks), the On NA only stage (24 weeks), and the NA cessation and durability stages (48 weeks) is up to approximately 104 weeks at maximum for each participant.”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.3-4"></a>

###### Two identically designed phase 3 trials in the prescribing information

> “The efficacy of HIBSAGO in the treatment of chronic HBV infection was evaluated in two multi-center, Phase 3, randomized, double-blind, placebo-controlled trials with identical designs (B-Well 1 [NCT05630807] and B-Well 2 [NCT05630820]).”
> “The randomization was stratified by HBsAg levels at baseline (HBsAg ≤ 1,000 IU/mL or >1,000 IU/mL to ≤3,000 IU/mL).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.3-5"></a>

###### Nucleos(t)ide analogue cessation at week 48 and cessation eligibility criteria

> “At Week 48, participants who met the prespecified NrtI cessation eligibility criteria discontinued NrtI therapy.”
> “To be eligible for NrtI cessation, participants had to have no evidence of cirrhosis at Week 36, have HBV DNA <LLOQ and HBsAg not detected (as assessed by the qualitative HBsAg assay) from Week 24 to 46 (allowing”
> “for single blips to any level) in the absence of rescue medication (defined as any medication with proven anti-HBV activity newly initiated for the purpose of HBV control), be HBeAg negative with ALT values ≤2x ULN at Week 46, and have remained on stable NrtI therapy for the preceding 48 weeks.”
> “Blips were defined as transiently quantifiable HBV DNA (≥LLOQ) or detected HBsAg at a single visit.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.3-6"></a>

###### Criteria to restart nucleos(t)ide analogue therapy after cessation

> “Protocol-defined criteria to restart NrtI therapy included HBV DNA >20,000 IU/mL at a single visit, HBV DNA >2,000 IU/mL at two sequential visits, confirmed HBeAg reversion, or clinical/hepatic decompensation.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.3-7"></a>

###### 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.”
> “Eligible patients discontinued NA therapy at 48 weeks.”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.1.3-8"></a>

###### Placebo control, treatment arms, and data monitoring committee in the EU Clinical Trials Register record

> “Therapeutic confirmatory (Phase III) Yes”
> “Placebo Yes”
> “Number of treatment arms in the trial 2”
> “Trial has a data monitoring committee Yes”

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="topic-3.1.1.3-9"></a>

###### Design of both B-Well trials stated by the company

> “The B-Well 1 and B-Well 2 trials are global multi-centre, randomised, double-blind, placebo-controlled trials conducted in 29 countries.”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="heading-3.1.1.4"></a>

##### 3.1.1.4 Eligibility Criteria

<a id="topic-3.1.1.4-1"></a>

###### Key inclusion and exclusion criteria summarized in the prescribing information

> “All participants were aged ≥18 years, had documented chronic HBV infection for ≥6 months, were receiving stable NrtI therapy (defined as no changes due to loss of virologic control for ≥6 months before the start of the trial and no plans for changes over the duration of the trial), and had serum HBsAg >100 to ≤3,000 IU/mL at screening, HBV DNA <90 IU/mL, and ALT ≤2X the upper limit of normal.”
> “Participants could be either HBeAg-positive or HBeAg-negative at baseline.”
> “Participants were excluded from the trial if they had a history, suspicion, or evidence of cirrhosis; co-infection with HCV, HIV, or HDV; history or evidence of potential vasculitis; eGFR ≤60 mL/min/1.73m2; or platelet count <140 x 109/L.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.4-2"></a>

###### Population described in the primary publication

> “All the patients were receiving stable nucleoside or nucleotide analogue (NA) therapy and had an HBsAg level of more than 100 to 3000 IU per milliliter.”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.1.4-3"></a>

###### Inclusion criteria in the ClinicalTrials.gov record

> “Participants who have documented chronic HBV infection ≥6 months prior to screening and currently receiving stable NA therapy defined as no changes to their NA regimen from at least 6 months prior to Screening and with no planned changes to the stable regimen over the duration of the study.”
> “Plasma or serum HBsAg concentration >100 IU/mL, but no greater than ≤3000 IU/mL.”
> “Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.”
> “Alanine aminotransferase (ALT) ≤2 × upper limit of normal (ULN).”
> “Participants who are willing and able to cease their NA treatment in accordance with the protocol.”
> “Ages Eligible for Study 18 Years and older”
> “Accepts Healthy Volunteers No”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.4-4"></a>

###### Exclusion criteria: coinfection, cirrhosis, malignancy, vasculitis, and extrahepatic disorders in the ClinicalTrials.gov record

> “Co-infection with: a) Current history of Hepatitis C infection or participants that have been cured for <12 months at the time of screening b) Human immunodeficiency virus (HIV), c) Hepatitis D virus.”
> “History of or suspected liver cirrhosis and/or evidence of cirrhosis.”
> “Diagnosed or suspected hepatocellular carcinoma.”
> “History of malignancy within the past 5 years except for specific cancers that are cured by surgical resection (e.g., skin cancer).”
> “History of vasculitis or presence of symptoms and signs of potential vasculitis (e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause) current or history of an autoimmune condition or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).”
> “History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).”
> “History of alcohol or drug abuse/dependence.”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.4-5"></a>

###### Exclusion criteria: prior and concomitant therapy in the ClinicalTrials.gov record

> “Currently taking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (≤2 weeks) or topical/inhaled steroid use.”
> “Currently taking, or has taken within 12 months of Screening, any interferon containing therapy.”
> “Participants requiring anti coagulation therapies (e.g., warfarin, Factor Xa inhibitors) or anti-platelet agents (like clopidogrel or aspirin) unless treatment can safely be discontinued throughout duration of the study, by the discretion of the investigator.”
> “Prior treatment with any oligonucleotide or siRNA within 12 months prior to the first dosing day.”
> “Prior treatment with bepirovirsen.”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.4-6"></a>

###### Definition of cirrhosis for exclusion in the EU Clinical Trials Register record

> “History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by”
> “Both APRI >2 and FibroSure/FibroTest result >0.7”
> “If only 1 parameter (APRI or FibroSure/FibroTest) result is positive, a discussion with the Medical Monitor is required before inclusion in study is permitted”
> “Liver biopsy (i.e., Metavir Score F4)”
> “Liver stiffness >12 kPa”

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="topic-3.1.1.4-7"></a>

###### Other exclusion criteria in the EU Clinical Trials Register record

> “Hepatitis D virus defined as HDV antibody positive”
> “Diagnosed or suspected hepatocellular carcinoma as evidenced by the following”
> “<200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomization.”
> “At least 18 years of age at the time of signing the informed consent”

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="heading-3.1.1.5"></a>

##### 3.1.1.5 Treatment

<a id="topic-3.1.1.5-1"></a>

###### Hibsago or placebo dosing regimen with background nucleos(t)ide analogue therapy

> “Participants were randomized 2:1 to receive HIBSAGO for 24 weeks (300 mg, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24), or placebo, together with their background NrtI therapy.”
> “Each dose of HIBSAGO was administered as two 150 mg subcutaneous injections into the abdomen, thigh, and/or outer area of upper arms.”
> “From Week 25 to 48, participants continued to receive their NrtI therapy without HIBSAGO or placebo.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.5-2"></a>

###### Dose and duration in the primary publication

> “subcutaneous bepirovirsen (at a weekly dose of 300 mg) or placebo for 24 weeks”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.1.5-3"></a>

###### 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.” |

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.5-4"></a>

###### Treatment arms in the company pipeline appendix

> “Arm A: bepirovirsen for 24 weeks”
> “Arm B: placebo”

Source: [GSK FY2025 pipeline assets and clinical trials appendix (2026)](https://www.gsk.com/media/rs0mbgqw/fy-2025-pipeline-assets-and-clinical-trials-report.pdf)

<a id="topic-3.1.1.5-5"></a>

###### 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.” |

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="heading-3.1.1.6"></a>

##### 3.1.1.6 Study Outcomes

<a id="heading-3.1.1.6.1"></a>

###### 3.1.1.6.1 Rationale for Using Functional Cure as the Primary Endpoint

<a id="topic-3.1.1.6.1-1"></a>

###### Registered primary outcome measure in the ClinicalTrials.gov record

> “Number of participants achieving functional cure (FC) with baseline HBsAg ≤3000 IU/mL”
> “The number of participants who achieved FC after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication will be reported.”
> “The FC for HBV is defined as Sustained suppression (24 weeks or longer) of HBV DNA < Lower limit of quantification (LLOQ) off all HBV treatment and HBsAg not detected with or without HBsAb after a finite duration of therapy.”
> “Up to 72 weeks”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.6.1-2"></a>

###### Registered secondary outcome measures in the ClinicalTrials.gov record

> “Number of participants achieving FC with baseline HBsAg ≤1000 IU/mL”
> “Number of participants achieving sustained suppression of HBV DNA (<LLOQ) with baseline HBsAg ≤3000 IU/mL”
> “Number of participants achieving sustained suppression of HBV DNA (<LLOQ) with baseline HBsAg ≤1000 IU/mL”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.6.1-3"></a>

###### Primary and secondary end points and time point in the EU Clinical Trials Register record

> “Functional cure for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg <3000IU/mL”
> “Functional cure for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg <1000IU/mL”
> “Sustained suppression of HBV DNA (<LLOQ) for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg <3000IU/mL”
> “Sustained suppression of HBV DNA (<LLOQ) for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg <1000 IU/mL”
> “Timepoint(s) of evaluation of this end point Week 72”

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="topic-3.1.1.6.1-4"></a>

###### Primary and three key secondary endpoints assessed at week 72 in the prescribing information

> “At Week 72, twenty-four weeks after possible cessation of NrtI treatment in eligible participants and 48 weeks after the last HIBSAGO dose, the primary and three key secondary efficacy endpoints were assessed.”
> “The primary efficacy endpoint was sustained suppression of HBV DNA (<LLOQ) and HBsAg not detected (LOD = 0.05 IU/mL), with or without hepatitis B surface antibodies, at 24 weeks after discontinuation of all chronic HBV treatment in the absence of rescue medication in participants with baseline HBsAg ≤3,000 IU/mL.”
> “The first key secondary endpoint was assessed by applying the same criteria to participants with baseline HBsAg ≤1,000 IU/mL.”
> “The second key secondary efficacy endpoint was sustained suppression of HBV DNA (<LLOQ), at 24 weeks after discontinuation of all chronic HBV treatment in the absence of rescue medication in participants with baseline HBsAg ≤3,000 IU/mL.”
> “The third key secondary endpoint was assessed by applying the same criteria of sustained suppression of HBV DNA (<LLOQ) to participants with baseline HBsAg ≤1,000 IU/mL.”
> “Blips in the Week 72 analysis window were permitted for the primary and key secondary endpoint analyses.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.6.1-5"></a>

###### Functional cure definition and assay thresholds in the company release

> “Defined as HBsAg not detected (qualitative; < 0.05 IU/mL) and HBV DNA < LLOQ (< 20 IU/mL or target not detected)”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.1.6.1-6"></a>

###### 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.”
> “The primary outcome was a functional cure at week 72.”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.1.6.1-7"></a>

###### 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.”
> “Moreover, HBsAg seroclearance is easy to measure with standardized and widely available assays.”
> “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.”

Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/)

<a id="topic-3.1.1.6.1-8"></a>

###### 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.”
> “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.”

Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/)

<a id="topic-3.1.1.6.1-9"></a>

###### 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.”

Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/)

<a id="topic-3.1.1.6.1-10"></a>

###### Efficacy endpoints and add-on placebo-controlled design for finite therapy: FDA guidance

> “HBsAg loss is considered the best predictor of sustained remission off-treatment”
> “To evaluate the primary efficacy outcome of sustained HBV DNA suppression off-treatment with HBsAg loss”
> “who are virally suppressed on NrtIs, sponsors can consider an add-on superiority trial against placebo with a current NrtI treatment regimen as the background therapy.”
> “It is expected that few subjects would meet such criteria on the placebo arm.”
> “For CHB, HBV DNA suppression with or without HBsAg loss is considered a validated surrogate endpoint that has been demonstrated to predict clinical outcomes”

Source: [FDA guidance on chronic hepatitis B drug development (2022)](https://www.fda.gov/media/117977/download)

<a id="topic-3.1.1.6.1-11"></a>

###### Functional cure as the primary endpoint of phase II/III trials: EASL clinical practice guideline

> “While the ultimate goal of treatment and the primary endpoint for phase II/III trials of finite treatments for chronic HBV infection is a "functional" cure, defined as sustained HBsAg loss (at least 24 weeks off therapy) with HBV DNA below the limit of quantification (LOQ), a sustained HBsAg level <100 IU/ml with HBV DNA <LOQ at 24 weeks off therapy is now being proposed as an alternative intermediate endpoint, or "partial cure".”
> “HBsAg loss is the ultimate goal of therapy.”

Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018)

<a id="topic-3.1.1.6.1-12"></a>

###### 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”
> “Functional cure is rare (≤ 5%) with NA therapy”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="heading-3.1.1.7"></a>

##### 3.1.1.7 Statistical Analysis Description

<a id="heading-3.1.1.7.1"></a>

###### 3.1.1.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.1.7.1-1"></a>

###### Planned number of participants in the EU Clinical Trials Register record

> “In the EEA 191”
> “In the whole clinical trial 900”
> “Number of subjects for this age range: 738”
> “Number of subjects for this age range: 162”

Source: [EU Clinical Trials Register 2021-005139-22](https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005139-22/GR)

<a id="topic-3.1.1.7.1-2"></a>

###### Actual enrollment in the ClinicalTrials.gov record

> “Enrollment (Actual) 981”

Source: [ClinicalTrials.gov NCT05630807](https://clinicaltrials.gov/study/NCT05630807)

<a id="topic-3.1.1.7.1-3"></a>

###### Subjects in the company pipeline appendix

> “NCT05630807 - B-WELL 1 Phase III Patient Non-cirrhotic nucleos(t)ide analogue treated patients with chronic hepatitis B virus Subjects 981”

Source: [GSK FY2025 pipeline assets and clinical trials appendix (2026)](https://www.gsk.com/media/rs0mbgqw/fy-2025-pipeline-assets-and-clinical-trials-report.pdf)

<a id="topic-3.1.1.7.1-4"></a>

###### Randomized participants and full analysis set in the prescribing information

> “In Trial B-Well 1, a total of 981 participants were randomized (2:1) to receive either HIBSAGO or placebo.”
> “In the full analysis set (FAS) of 978 participants who received at least one dose of HIBSAGO or placebo”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.7.1-5"></a>

###### Participants analyzed for the primary and first key secondary endpoints by treatment group

| Analysis population | Hibsago (n/N) | Placebo (n/N) |
| --- | --- | --- |
| Baseline HBsAg up to 3,000 IU/mL (primary endpoint) | “127/650” | “0/328” |
| Baseline HBsAg up to 1,000 IU/mL (first key secondary endpoint) | “105/426” | “0/214” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.7.1-6"></a>

###### Participants analyzed for the primary endpoint in the primary publication

> “in the B-Well 1 trial (in 127 of 650 patients [20%] vs. none of 328 patients)”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.1.7.1-7"></a>

###### Pooled B-Well 1 and B-Well 2 results: participants in both trials

> “evaluating bepirovirsen, an investigational antisense oligonucleotide (ASO) for the treatment of chronic hepatitis B (CHB) in over 1,800 patients from 29 countries.”

Source: [GSK press release, B-Well topline (2026)](https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-results-from-b-well-1-and-b-well-2-phase-iii-trials-for-bepirovirsen-a-potential-first-in-class-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.1.7.1-8"></a>

###### Pooled B-Well 1 and B-Well 2 results: participants in the pooled safety population

> “The safety of HIBSAGO in the treatment of chronic HBV infection has been evaluated in two pooled, Phase 3, placebo-controlled randomized trials (B-Well 1 and B-Well 2) in which 1,223 participants received at least one dose of HIBSAGO (300 mg subcutaneously, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24) and 611 participants received matching placebo.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.1.7.2"></a>

###### 3.1.1.7.2 Description of Analysis Sets

<a id="topic-3.1.1.7.2-1"></a>

###### Full analysis set used for efficacy

> “In the full analysis set (FAS) of 978 participants who received at least one dose of HIBSAGO or placebo”
> “Not Detected at 24 Weeks after Cessation of NrtI Treatment (FAS Population)”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.7.2-2"></a>

###### Statistical methods for the primary endpoint: stratified common rate difference and exact Cochran-Mantel-Haenszel test

> “Common rate difference, calculated as a weighted average of the stratum-specific rate differences, with the associated 95% confidence interval (CI) from stratified Miettinen-Nurminen method.”
> “Based on two-sided p-value (exact Cochran-Mantel Haenszel).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.7.2-3"></a>

###### Statistical methods for the key secondary endpoints in participants with baseline HBsAg up to 1,000 IU/mL

> “95% Miettinen-Nurminen confidence interval (CI).”
> “Based on two-sided p-value (Boschloo's test).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.7.2-4"></a>

###### Ranked order of the primary and key secondary endpoints

> “A key ranked secondary endpoint evaluated functional cure in participants with baseline HBsAg ≤1000 IU/ml.”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.1.7.2-5"></a>

###### Pooled B-Well 1 and B-Well 2 results: pooled safety data set, weeks 1 to 36

> “The incidence of adverse reactions in the pooled safety data set (Weeks 1-36) with HIBSAGO is shown in Table 4.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.7.2-6"></a>

###### Pooled B-Well 1 and B-Well 2 results: subgroup analyses of the pooled population

> “Figure 1. Subgroup Analyses of Sustained Suppression of HBV DNA and HBsAg Not Detected at 24 Weeks after Cessation of NrtI Treatment, by Selected Baseline Factors (Pooled Population from B-Well 1 and B-Well 2).”
> “Overall: results are based on pooled data; Rate Difference: common rate difference (Miettinen-Nurminen method)”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.7.2-7"></a>

###### Pooled B-Well 1 and B-Well 2 results: post hoc analysis of predictors of nonresponse

> “A post-hoc exploratory analysis was conducted using the pooled data from B-Well 1 and B-Well 2 trials to determine predictors associated with nonresponse to treatment.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.7.2-8"></a>

###### Pooled B-Well 1 and B-Well 2 results: durability population of participants who stopped nucleos(t)ide analogue therapy

> “HIBSAGO recipients who met the criteria to discontinue NrtI therapy and discontinued NrtI therapy at Week 48 (295/1,220 across both trials) were monitored for an additional 48 weeks with assessments at Week 72 to assess the primary endpoint and Week 96 to evaluate the long-term durability of response (sustained HBV DNA <LLOQ and HBsAg not detected [LOD = 0.05 IU/mL] off all HBV treatment).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

Additional sources: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="heading-3.1.1.8"></a>

##### 3.1.1.8 Results

<a id="heading-3.1.1.8.1"></a>

###### 3.1.1.8.1 Participant Disposition

<a id="topic-3.1.1.8.1-1"></a>

###### Randomized participants and full analysis set

> “In Trial B-Well 1, a total of 981 participants were randomized (2:1) to receive either HIBSAGO or placebo.”
> “In the full analysis set (FAS) of 978 participants who received at least one dose of HIBSAGO or placebo”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.1-2"></a>

###### Pooled B-Well 1 and B-Well 2 results: participants who received at least one dose

> “in which 1,223 participants received at least one dose of HIBSAGO (300 mg subcutaneously, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24) and 611 participants received matching placebo.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.1-3"></a>

###### Pooled B-Well 1 and B-Well 2 results: participants who stopped NrtI therapy at week 48

> “HIBSAGO recipients who met the criteria to discontinue NrtI therapy and discontinued NrtI therapy at Week 48 (295/1,220 across both trials) were monitored for an additional 48 weeks”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

> “Across the two trials, 24% of patients who received Hibsago met the requirements to stop their existing medicine, compared with none who received placebo.”

Source: [FDA Hibsago approval announcement (2026)](https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-chronic-hepatitis-b-treatment)

Additional sources: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="heading-3.1.1.8.2"></a>

###### 3.1.1.8.2 Baseline Characteristics

<a id="topic-3.1.1.8.2-1"></a>

###### Demographics: sex, age, race, and ethnicity

> “70% were male; the mean age was 50 years (range: 21 to 87 years); 68% were Asian, 25% were White, 5% were Black or African American, and 2% were Other; 11% were Hispanic or Latino”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.2-2"></a>

###### Geographic region of enrollment

> “58% were in Asia, 25% were in Europe, 10% were in Latin America, and 7% were in US and Canada”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.2-3"></a>

###### Baseline HBsAg level and HBV genotype

> “65% had HBsAg at baseline ≤1,000 IU/mL; 31% were genotype C, 26% were genotype D, 25% were genotype B, 10% were genotype A, 8% were other genotypes”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.2-4"></a>

###### Baseline ALT and HBeAg status

> “91% had ALT ≤ULN at baseline; 92% were HBeAg negative at baseline”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.2-5"></a>

###### Time since chronic hepatitis B diagnosis

> “41% had been diagnosed with CHB for 20 years or longer, 33% for 10 to 20 years, 15% for 5 to 10 years, and 11% were diagnosed less than 5 years ago.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.2-6"></a>

###### Balance between treatment groups

> “In each trial, demographic characteristics were generally balanced between HIBSAGO and placebo participants.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.2-7"></a>

###### Pooled B-Well 1 and B-Well 2 results: participants aged 65 years and older

> “Of the total number of patients who received treatment with HIBSAGO in the B-Well 1 and B-Well 2 trials, 128 (10%) were 65 years of age and older.”
> “In the B-Well 1 and B-Well 2 trials, 21 (1%) participants were 75 years of age and older.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

Additional sources: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="heading-3.1.1.8.3"></a>

###### 3.1.1.8.3 Efficacy Results

<a id="topic-3.1.1.8.3-1"></a>

###### Primary and key secondary endpoints met

> “Within both trials, the primary and key secondary endpoints were met.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.3-2"></a>

###### 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” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

> “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)”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.1.8.3-3"></a>

###### 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” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.3-4"></a>

###### 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” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.3-5"></a>

###### 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” |

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

> “Twenty-four weeks after stopping all hepatitis B treatment, 19% of patients who received Hibsago still had the virus under control, and a protein that signals hepatitis B infection (HBsAg) could not be detected in their blood.”

Source: [FDA Hibsago approval announcement (2026)](https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-chronic-hepatitis-b-treatment)

<a id="topic-3.1.1.8.3-6"></a>

###### Pooled B-Well 1 and B-Well 2 results: sustained HBV DNA suppression below the LLOQ

> “Moreover, 23% of all bepirovirsen recipients (283 of 1220 vs 0 of 614 in the placebo group; p<0.001 in both trials) and 31% of bepirovirsen recipients with baseline HBsAg ≤1000 IU/mL (237 of 768 vs 0 of 393 in the placebo group; p<0.001 in both trials) achieved a sustained HBV DNA lower limit of quantification (<LLOQ) at week 72 after stopping all treatment at week 48 in a key secondary endpoint.”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.1.8.3-7"></a>

###### Pooled B-Well 1 and B-Well 2 results: HBsAg at or below 100 IU/mL, exploratory analysis

> “Exploratory analyses also showed bepirovirsen reduced HBsAg to ≤100 IU/ml in 49% of participants (598 of 1220) in the overall study population, and in 62% of bepirovirsen recipients in the ≤1000 IU/ml (476 of 768) sub-group”
> “as of the week 72 visit.”

Source: [GSK press release, Hibsago US approval (2026)](https://www.gsk.com/en-gb/media/press-releases/hibsago-bepirovirsen-approved-in-the-us-for-the-treatment-of-chronic-hepatitis-b-chb/)

<a id="topic-3.1.1.8.3-8"></a>

###### Pooled B-Well 1 and B-Well 2 results: subgroups with lower response

> “The primary endpoint response rate was lower in participants with any of the following characteristics: higher HBsAg values at baseline, HBeAg positive at baseline, and age 65 years or older (see Figure 1).”
> “The efficacy response was generally higher for age <65 versus that for age ≥65 years”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.3-9"></a>

###### Pooled B-Well 1 and B-Well 2 results: response by HBV genotype

> “In pooled data from the B-Well 1 and B-Well 2 clinical trials, rates of sustained off-treatment suppression of HBV DNA below the lower limit of quantification (20 IU/mL) and HBsAg not detected (LOD = 0.05 IU/mL) at 24 weeks off all HBV treatment among participants who received HIBSAGO varied by HBV genotype and baseline HBsAg level.”
> “Overall response rates were 28% for genotype A, 21% for genotype B, 20% for genotype D, and 15% for genotype C.”
> “Response rates declined with increasing baseline HBsAg levels and fell below 10% for genotypes B and C at baseline HBsAg levels exceeding 1,000 IU/mL.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.3-10"></a>

###### 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

> “A post-hoc exploratory analysis was conducted using the pooled data from B-Well 1 and B-Well 2 trials to determine predictors associated with nonresponse to treatment.”
> “An early on-treatment response defined as HBsAg <1 IU/mL at Treatment Week 12 was identified as a predictor of achieving the primary efficacy endpoint with HIBSAGO treatment”
> “Among participants with baseline HBsAg ≤3,000 IU/mL who met this criterion, 34% (203/601) had sustained suppression of HBV DNA and HBsAg not detected at 24 weeks after cessation of all chronic HBV treatment.”
> “Participants who did not meet this criterion (who had HBsAg ≥1 IU/mL at Week 12) had a 2% (9/498) probability of having sustained suppression of HBV DNA and HBsAg not detected at 24 weeks after cessation of all chronic HBV treatment.”
> “Among participants with baseline HBsAg ≤1,000 IU/mL who met this criterion, 42% (179/426) achieved this endpoint, and those who did not meet this criterion had a 2.5% (7/280) probability of achieving this endpoint.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.3-11"></a>

###### Pooled B-Well 1 and B-Well 2 results: durability of response at weeks 72 and 96 after NrtI cessation

> “At Week 72, 24 weeks after stopping NrtI therapy, 79% (233/295) of these participants met the primary endpoint.”
> “Of the 233 participants who met the primary endpoint at Week 72, 91% (211/233) maintained response off all HBV treatment at Week 96.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.3-12"></a>

###### Pooled B-Well 1 and B-Well 2 results: NrtI restart through week 96

> “Through Week 96, among the 84 HIBSAGO recipients who discontinued NrtI therapy but did not achieve the primary endpoint at Week 72 (62 participants) or who achieved the primary endpoint but did not maintain a sustained response at Week 96 (22 participants), one participant met criteria to restart NrtI therapy.”
> “Out of the 84 participants, three additional participants restarted NrtI therapy within one month of NrtI cessation without having met the protocol-defined NrtI restart criteria.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.3-13"></a>

###### 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)” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.1.8.4"></a>

###### 3.1.1.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.1.8.5"></a>

###### 3.1.1.8.5 Safety Results

<a id="topic-3.1.1.8.5-1"></a>

###### 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.”
> “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).”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.1.8.5-2"></a>

###### Pooled B-Well 1 and B-Well 2 results: discontinuation due to adverse events

> “In the pooled B-Well 1 and B-Well 2 trials, 3% of participants receiving HIBSAGO and <1% of participants receiving placebo discontinued due to adverse events.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-3"></a>

###### Pooled B-Well 1 and B-Well 2 results: adverse reactions in at least 3% of Hibsago recipients, weeks 1 to 36

| Adverse reaction | Hibsago (N = 1,223) | Placebo (N = 611) |
| --- | --- | --- |
| Injection site reactions (all types) | “57%” | “15%” |
| Pyrexia | “20%” | “4%” |
| Fatigue | “16%” | “8%” |
| Headache | “14%” | “12%” |
| Myalgia | “8%” | “4%” |
| Nausea or vomiting | “5%” | “3%” |
| Erythema | “5%” | “<1%” |
| Pruritus | “5%” | “2%” |
| Influenza-like illness | “4%” | “2%” |
| Rash | “3%” | “1%” |
| Contusion | “3%” | “1%” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

> “Fatigue includes the preferred terms asthenia, fatigue, malaise, lethargy and sluggishness.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-4"></a>

###### Pooled B-Well 1 and B-Well 2 results: injection site reactions, weeks 1 to 36

| Injection site reaction | Hibsago (N = 1,223) | Placebo (N = 611) |
| --- | --- | --- |
| Any injection site reaction | “57%” | “15%” |
| Erythema | “32%” | “2%” |
| Pain | “24%” | “6%” |
| Pruritus | “19%” | “1%” |
| Bruising | “19%” | “6%” |
| Induration or swelling | “13%” | “1%” |
| Discoloration | “8%” | “<1%” |
| Rash | “6%” | “<1%” |
| Hematoma | “4%” | “1%” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

> “The frequency and severity of injection site reactions decreased over time, and 99% of injection site reactions reported in HIBSAGO recipients were mild to moderate in severity.”
> “A serious adverse reaction of omental infarction requiring surgical intervention occurred at Treatment Week 11 in a participant who had four weeks of persistent erythema at the HIBSAGO injection site and in whom injection sites had not been rotated.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-5"></a>

###### 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%” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-6"></a>

###### Pooled B-Well 1 and B-Well 2 results: ALT increases leading to treatment pause or discontinuation

> “During the first 24 weeks, <1% (n = 1) of HIBSAGO recipients had ALT ≥3x ULN with bilirubin ≥2x ULN (>35% direct bilirubin) and permanently discontinued treatment”
> “Three other participants also permanently discontinued treatment because of ALT ≥10 x ULN for 4 or more weeks, and 53 (4%) paused treatment due to ALT increases.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-7"></a>

###### Pooled B-Well 1 and B-Well 2 results: thrombocytopenia and platelet count decline

> “During the first 24 weeks, two participants treated with HIBSAGO had serious adverse reactions of thrombocytopenia, with platelet counts <50 × 10⁹/L.”
> “This participant was assessed as having immune thrombocytopenia. Both participants recovered with corticosteroid treatment and permanent discontinuation of HIBSAGO”
> “In total, 8 (<1%) participants met permanent discontinuation criteria, and 114 (9%) participants paused treatment due to platelet declines.”
> “In the pivotal clinical trials, the maximum change from baseline in platelet count in the HIBSAGO group occurred at Week 24, with a mean (SD) change from baseline of -68 x 109/L (40.7) or -28.1% (13.79), from a baseline of 233 x 109/L.”
> “The mean platelet count in the HIBSAGO group recovered to within 5% of baseline values by Week 60 (36 weeks after last dose of HIBSAGO).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-8"></a>

###### Pooled B-Well 1 and B-Well 2 results: neutrophil count decline

> “During the first 24 weeks, 27 (2%) of participants had neutrophil counts <1,000 cells/mm3 at 2 or more consecutive visits. No participant had a value <500 cells/mm3 at 2 or more consecutive visits.”
> “The decline in neutrophil count was not associated with adverse events that indicated increased risk of infection.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-9"></a>

###### Pooled B-Well 1 and B-Well 2 results: eGFR decline

> “During the first 24 weeks, in participants treated with HIBSAGO, 4% had an eGFR decrease >30% of pretreatment levels for 2 or more consecutive readings and <1% (one participant) experienced such declines more than 24 weeks after completion of HIBSAGO treatment”
> “No participant met criteria for permanent discontinuation of HIBSAGO treatment based on decreased renal function, but 28 (2%) participants paused treatment because of decreased renal function.”
> “In the pivotal clinical trials, the maximum change from baseline in eGFR in the HIBSAGO group occurred at Week 25, with a mean (SD) change from baseline of -10 mL/min/1.73 m2 (9.96) or -10% (10.28), from a baseline of 100.8 mL/min/1.73m2.”
> “The mean eGFR in the HIBSAGO group recovered to within 5% of baseline values by Week 36 (12 weeks after last dose of HIBSAGO).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-10"></a>

###### Pooled B-Well 1 and B-Well 2 results: cutaneous vasculitis

> “Adverse reactions of biopsy-confirmed vasculitis occurred in two participants treated with HIBSAGO.”
> “leukocytoclastic vasculitis, and the events resolved with corticosteroid treatment after permanent discontinuation of HIBSAGO”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-11"></a>

###### Less common adverse reactions: hypersensitivity and angioedema

> “The following adverse reactions occurred in <3% of participants receiving HIBSAGO and are included because of a potential causal relationship:”
> “Immune system disorders: Hypersensitivity”
> “Skin and soft tissue disorders: Angioedema”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-12"></a>

###### Pooled B-Well 1 and B-Well 2 results: anti-drug antibodies

> “In the Phase 3 B-Well trials, 43% (517/1,203) of participants treated with HIBSAGO tested positive for ADAs.”
> “The presence of ADAs resulted in a 26.6% lower systemic clearance of bepirovirsen. The development of these antibodies did not appear to be associated with a reduced treatment response or differences in the safety profile.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-13"></a>

###### Safety in participants aged 65 years and older

> “No overall differences in safety of HIBSAGO were observed between patients 65 years of age and older and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.8.5-14"></a>

###### Most frequently observed adverse events

> “The trials showed an acceptable safety and tolerability profile consistent with other studies of bepirovirsen. The three most frequently observed adverse events were injection site erythema, local pain and temporary rise in the blood level of a liver enzyme.”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="heading-3.1.1.9"></a>

##### 3.1.1.9 Study Limitations

<a id="topic-3.1.1.9-1"></a>

###### 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.

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF); [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.1.9-2"></a>

###### Small number of participants aged 75 years and older

> “Differences in efficacy in this age group versus younger adult patients cannot be determined due to the small number of participants.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.9-3"></a>

###### Exclusion of moderate or severe renal impairment

> “The clinical trials excluded participants with moderate or severe renal impairment (eGFR ≤60 mL/min/1.73m2) or uACR >0.3 mg/mg; insufficient data are available on the safety of HIBSAGO in these populations”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.9-4"></a>

###### No data in hepatitis D virus coinfection or on transmission

> “There are no data on the safety and efficacy of HIBSAGO in patients with HBV and hepatitis D virus (HDV) coinfection.”
> “There are no data on the effect of HIBSAGO in preventing transmission of HBV.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.1.9-5"></a>

###### Unknown clinical impact of binding-site variants with reduced susceptibility

> “The clinical impact of reduced susceptibility to HIBSAGO in these variants is unknown.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

Additional sources: [Lok (2026)](https://pubmed.ncbi.nlm.nih.gov/42206569/); [Hou et al. (2026b)](https://pubmed.ncbi.nlm.nih.gov/42777251/); [Pirzada et al. (2026)](https://pubmed.ncbi.nlm.nih.gov/42832798/); [Lens (2026)](https://pubmed.ncbi.nlm.nih.gov/42480667/)

<a id="heading-3.1.2"></a>

#### 3.1.2 B-Well 2

<a id="heading-3.1.2.1"></a>

##### 3.1.2.1 Objective

<a id="topic-3.1.2.1-1"></a>

###### Purpose stated in the ClinicalTrials.gov brief summary

> “This study is intended to confirm the efficacy, safety, pharmacokinetic (PK) profile, and the durability of hepatitis B virus surface antigen (HBsAg) suppression observed with bepirovirsen for 24 weeks (with loading doses) as compared to the placebo arm.”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.1-2"></a>

###### Main objective in the EU Clinical Trials Information System record

> “To assess the treatment effect of 24 weeks bepirovirsen with loading doses to achieve functional cure in participants with chronic HBV infection on NA treatment with baseline HBsAg ≤3000 IU/mL”

Source: [EU Clinical Trials Information System 2023-504238-23-00](https://euclinicaltrials.eu/ctis-public/view/2023-504238-23-00)

<a id="topic-3.1.2.1-3"></a>

###### Main and secondary objectives in the EU Clinical Trials Register record

> “Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses to achieve functional cure in participants with chronic HBV infection on-NA treatment with baseline HBsAg ≤3000 IU/mL”
> “Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses to achieve functional cure in participants with chronic HBV infection on NA treatment with baseline HBsAg ≤1000 IU/mL”
> “Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses in HBV DNA suppression off-treatment after a finite duration of therapy in participants with chronic HBV infection on NA treatment with baseline HBsAg ≤3000 IU/mL”
> “Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses in HBV DNA suppression after a finite duration of therapy in participants with chronic HBV infection on NA treatment with baseline HBsAg ≤1000 IU/mL”
> “Safety: To assess the safety and tolerability of bepirovirsen when dosed for 24 weeks duration with loading doses in participants with chronic HBV infection on NA treatment”

Source: [EU Clinical Trials Register 2022-002268-53](https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002268-53/BG)

<a id="topic-3.1.2.1-4"></a>

###### Trial description in the company pipeline appendix

> “A multicentre, randomised, double blind trial to confirm the efficacy and safety of treatment with bepirovirsen in participants with chronic hepatitis B virus”

Source: [GSK FY2025 pipeline assets and clinical trials appendix (2026)](https://www.gsk.com/media/rs0mbgqw/fy-2025-pipeline-assets-and-clinical-trials-report.pdf)

<a id="topic-3.1.2.1-5"></a>

###### Aims of both B-Well trials stated by the company

> “They assessed the efficacy, safety, pharmacokinetic profile, and durability of functional cure in nucleos(t)ide analogue-treated adult participants with chronic hepatitis B and baseline surface antigen (HBsAg) ≤3000 IU/ml.”

Source: [GSK press release, Hibsago US approval (2026)](https://www.gsk.com/en-gb/media/press-releases/hibsago-bepirovirsen-approved-in-the-us-for-the-treatment-of-chronic-hepatitis-b-chb/)

<a id="heading-3.1.2.2"></a>

##### 3.1.2.2 Location and Study Date

<a id="topic-3.1.2.2-1"></a>

###### Study dates and status in the ClinicalTrials.gov record

> “Study Start (Actual) 2022-12-06”
> “Primary Completion (Actual) 2025-11-03”
> “Study Completion (Actual) 2026-04-13”
> “First Posted 2022-11-30”
> “Last Update Posted 2026-07-08”
> “Completed”
> “No Results Posted”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.2-2"></a>

###### Number of locations in the ClinicalTrials.gov record

> “This study has 171 locations”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.2-3"></a>

###### Study locations by country in the ClinicalTrials.gov record

| Country | Locations listed in the record |
| --- | --- |
| United States | “Centreville, Alabama, United States, 35042”; “Los Angeles, California, United States, 90033”; “San Francisco, California, United States, 94115”; “San Francisco, California, United States, 94121”; “Colorado Springs, Colorado, United States, 80907”; “Ft. Pierce, Florida, United States, 34982”; “Miami, Florida, United States, 33136”; “Glen Burnie, Maryland, United States, 21061”; “Minneapolis, Minnesota, United States, 55404”; “Philadelphia, Pennsylvania, United States, 19104”; “Denison, Texas, United States, 75020”; “Seattle, Washington, United States, 98104” |
| Argentina | “Buenos Aires, Argentina, 1023”; “Buenos Aires, Argentina, C1425AGC”; “Ciudad Autonoma de Bueno, Argentina, C1056ABI”; “Santa Fe, Argentina, 3000” |
| Australia | “Westmead, New South Wales, Australia, 2145”; “Herston, Queensland, Australia, 4029”; “Box Hill, Victoria, Australia, 3128”; “Fitzroy, Victoria, Australia, 3065” |
| Brazil | “Botucatu, Brazil, 18618-686”; “Fortaleza, Brazil, 60430-372”; “Nova Iguaçu, Brazil, 26030-380”; “Porto Alegre, Brazil, 90020-090”; “Porto Alegre, Brazil, 90035003”; “Rio de Janeiro, Brazil, 21045-900”; “Salvador, Brazil, 40110160”; “Vitória, Brazil, 29043260” |
| Bulgaria | “Plovdiv, Bulgaria, 4002”; “Sliven, Bulgaria, 8800”; “Sofia, Bulgaria, 1797”; “Varna, Bulgaria, 9020” |
| Canada | “Calgary, Alberta, Canada, T2N 4N1”; “Edmonton, Alberta, Canada, T6G 2B7”; “Edmonton, Alberta, Canada, T6G 2X8”; “Halifax, Nova Scotia, Canada, B3H 2Y9”; “Toronto, Ontario, Canada, M6H 3M1”; “Montreal, Quebec, Canada, H2L 4E9”; “Montreal, Quebec, Canada, H2L 4P9”; “Regina, Saskatchewan, Canada, S4P 0W5” |
| China | “Beijing, China, 100015”; “Beijing, China, 100032”; “Changchun, China, 130021”; “Chengdu, China, 610072”; “Chongqing, China, 400042”; “Guangzhou, China, 510515”; “Guangzhou, China, 510630”; “Hangzhou, China, 310003”; “Hangzhou, China, 310022”; “Hefei, China, 230022”; “Kunming, China, 650021”; “Liuzhou, China, 545006”; “Nanjing, China, 210003”; “Shanghai, China, 200025”; “Shanghai, China, 200052”; “Shenzhen, China, 518112”; “Taiyuan, China, 030001”; “Tianjin, China, 300000”; “Ürümqi, China, 830054”; “Wuhan, China, 430022”; “Xi'an, China, 710061”; “Xiamen, China, 361015”; “Zhengzhou, China, 450000”; “Zunyi, China, 563114” |
| France | “Créteil, France, 94010”; “Grenoble, France, 38043”; “Limoges, France, 87042”; “Lyon, France, 69317”; “Paris, France, 75651”; “Rouen, France, 76031”; “Toulouse, France, 31059” |
| Germany | “Frankfurt, Germany, 60329”; “Frankfurt, Germany, 60596”; “Hamburg, Germany, 20146”; “Hanover, Germany, 30625” |
| Greece | “Athens, Greece, 115 27”; “Heraklion Crete, Greece, 715 00”; “Thessaloniki, Greece, 54642” |
| Hungary | “Szeged, Hungary, 6725”; “Székesfehérvár, Hungary, 8000”; “Zalaegerszeg, Hungary” |
| India | “Ahmedabad, India, 380009”; “Chennai, India, 600035”; “Kanpur, India, 208002”; “Kochi, India, 682026”; “Kolkata, India, 700150”; “Kolkata, India”; “Mumbai, India, 400012”; “Mumbai, India, 400022”; “Nagpur, India, 441108”; “New Delhi, India, 110029”; “New Delhi, India, 110060”; “New Delhi, India, 110070”; “Pune, India, 411001”; “Raipur, India”; “Secunderabad, India, 500003” |
| Italy | “Milan, Italy, 20157”; “Naples, Italy, 80131”; “Padova, Italy, 35128”; “Palermo, Italy, 90127”; “Pisa, Italy, 56124”; “Roma, Italy, 00133”; “Sassari, Italy, 07100”; “Torino, Italy, 10126” |
| Japan | “Fukui, Japan, 918-8503”; “Hiroshima, Japan, 730-8619”; “Hokkaido, Japan, 006-8555”; “Hokkaido, Japan, 060-8648”; “Hokkaido, Japan, 062-8618”; “Ishikawa, Japan, 920-8650”; “Kagawa, Japan, 760-8557”; “Kumamoto, Japan, 860-8556”; “Nagasaki, Japan, 856-8562”; “Nara, Japan, 634-8522”; “Niigata, Japan, 950-1104”; “Osaka, Japan, 565-0871”; “Tokyo, Japan, 113-8603”; “Yamaguchi, Japan, 750-0061”; “Yamanashi, Japan, 409-3898” |
| Malaysia | “Johor Bahru, Malaysia, 80100”; “Kota Bharu Kelantan, Malaysia”; “Kota Kinabalu, Malaysia”; “Kuala Lumpur, Malaysia, 59100”; “Kuala Terengganu, Malaysia, 20400”; “Kuantan, Malaysia, 25100” |
| Mexico | “Aguascalientes, Mexico, 20010” |
| New Zealand | “Auckland, New Zealand, 1023”; “Auckland, New Zealand, 2025” |
| Panama | “Panama City, Panama” |
| Philippines | “Cebu City, Philippines, 6000”; “Makati City, Philippines, 1229”; “Pasig, Philippines, 1605”; “Silang, Philippines, 4118” |
| Poland | “Gdansk, Poland, 80-405”; “Mysłowice, Poland, 41-400”; “Żychlin, Poland, 62-571” |
| Romania | “Bucharest, Romania, 020475”; “Bucharest, Romania, 030303”; “Cluj-Napoca, Romania, 400348”; “Constanța, Romania, 900709”; “Galati, Romania, 800179”; “Oradea, Romania, 410469” |
| South Korea | “Ansan, South Korea, 15355”; “Incheon, South Korea, 405-760”; “Pusan, South Korea, 49241”; “Seoul, South Korea, 03312”; “Seoul, South Korea, 05505”; “Ulsan, South Korea, 44033” |
| Spain | “Alcorcon Madrid, Spain”; “Badajoz, Spain, 06080”; “Granada, Spain, 18016”; “Madrid, Spain, 28006”; “Madrid, Spain, 28032”; “Madrid, Spain, 28046”; “Sabadell Barcelona, Spain, 08208”; “Seville, Spain, 41013”; “Valencia, Spain, 46026”; “Valladolid, Spain, 47012”; “Zaragoza, Spain, 50009” |
| Taiwan | “Kaohsiung City, Taiwan, 824”; “Taichung, Taiwan, 404”; “Tainan, Taiwan, 704”; “Taipei, Taiwan, 100” |
| Thailand | “Chiang Mai, Thailand, 50200” |
| Turkey (Türkiye) | “Ankara, Turkey (Türkiye), 06590”; “Istanbul, Turkey (Türkiye), 34010”; “Izmir, Turkey (Türkiye), 35100” |
| United Kingdom | “Liverpool, United Kingdom, L7 8XP”; “London, United Kingdom, WC1E 6JB”; “Middlesbrough, United Kingdom, TS4 3BW”; “Newcastle upon Tyne, United Kingdom, NE7 7DN” |

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.2-4"></a>

###### EU and EEA member states, trial start, and end of trial in the EU Clinical Trials Information System record

> “Locations Germany, Spain, Greece, Hungary, Italy, Poland, Romania, Bulgaria, France”
> “Start of trial 17/01/2023”
> “End of trial 20/10/2025”
> “Global end of trial 13/04/2026”
> “Estimated recruitment start date in EU/EEA: 21/12/2022”

Source: [EU Clinical Trials Information System 2023-504238-23-00](https://euclinicaltrials.eu/ctis-public/view/2023-504238-23-00)

<a id="topic-3.1.2.2-5"></a>

###### Planned sites in the European Economic Area and regulatory and ethics decisions in the EU Clinical Trials Register record

> “Number of sites anticipated in the EEA 50”
> “Trial being conducted both within and outside the EEA Yes”
> “Date of Competent Authority Decision 2023-03-14”
> “Date of Ethics Committee Opinion 2023-02-09”

Source: [EU Clinical Trials Register 2022-002268-53](https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002268-53/BG)

<a id="topic-3.1.2.2-6"></a>

###### Countries in both B-Well trials stated by the company

> “B-Well 1 and B-Well 2 trials are global multi-centre, randomised, double-blind, placebo-controlled trials conducted in 29 countries.”

Source: [GSK press release, B-Well topline (2026)](https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-results-from-b-well-1-and-b-well-2-phase-iii-trials-for-bepirovirsen-a-potential-first-in-class-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.2.2-7"></a>

###### Trial start in the company pipeline appendix

> “Trial start: Q4 2022”

Source: [GSK FY2025 pipeline assets and clinical trials appendix (2026)](https://www.gsk.com/media/rs0mbgqw/fy-2025-pipeline-assets-and-clinical-trials-report.pdf)

<a id="topic-3.1.2.2-8"></a>

###### Initiation of the two phase 3 studies announced by the licensor

> “CARLSBAD, Calif., Feb. 1, 2023 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced that GSK has initiated two randomized, double-blind, placebo-controlled Phase 3 studies evaluating the safety and efficacy of bepirovirsen (formerly IONIS-HBVRx), an investigational antisense medicine for the treatment of patients with chronic hepatitis B infection (CHB).”

Source: [Ionis press release, phase 3 start (2023)](https://ir.ionis.com/node/29351)

<a id="heading-3.1.2.3"></a>

##### 3.1.2.3 Study Design

<a id="topic-3.1.2.3-1"></a>

###### Official title in the ClinicalTrials.gov record

> “Phase 3 Multicenter, Randomized, Double-Blind, Study to Assess the Efficacy and Safety of Treatment With Bepirovirsen in Nucleos(t)Ide Analogue-treated Participants With Chronic Hepatitis B Virus (B-Well 2)”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.3-2"></a>

###### 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.” |

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.3-3"></a>

###### Four study stages, stratification, and total duration in the ClinicalTrials.gov record

> “This study will have 4 stages: a) Double-blind treatment (bepirovirsen or placebo) for 24 weeks. b) Nucleos(t)ide analogue (NA) treatment for 24 weeks. c) NA cessation stage OR Continue NA for 24 weeks. d) Durability of response and follow up for further 24 weeks for participants who stopped NA treatment at Week 48.”
> “The arms will be stratified based on HBsAg level (HBsAg greater than or equal to [≥] 100 international unit per milliliter [IU/mL] to less than or equal [≤]1000 IU/mL or greater than [>] 1000 IU/mL to ≤3000 IU/mL) at screening.”
> “The total duration of the study, including screening (up to 60 days), the double-blind treatment stage (24 weeks), the On NA only stage (24 weeks), and the NA cessation and durability stages (48 weeks) is up to approximately 104 weeks at maximum for each participant.”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.3-4"></a>

###### Two identically designed phase 3 trials in the prescribing information

> “The efficacy of HIBSAGO in the treatment of chronic HBV infection was evaluated in two multi-center, Phase 3, randomized, double-blind, placebo-controlled trials with identical designs (B-Well 1 [NCT05630807] and B-Well 2 [NCT05630820]).”
> “The randomization was stratified by HBsAg levels at baseline (HBsAg ≤ 1,000 IU/mL or >1,000 IU/mL to ≤3,000 IU/mL).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.3-5"></a>

###### Nucleos(t)ide analogue cessation at week 48 and cessation eligibility criteria

> “At Week 48, participants who met the prespecified NrtI cessation eligibility criteria discontinued NrtI therapy.”
> “To be eligible for NrtI cessation, participants had to have no evidence of cirrhosis at Week 36, have HBV DNA <LLOQ and HBsAg not detected (as assessed by the qualitative HBsAg assay) from Week 24 to 46 (allowing”
> “for single blips to any level) in the absence of rescue medication (defined as any medication with proven anti-HBV activity newly initiated for the purpose of HBV control), be HBeAg negative with ALT values ≤2x ULN at Week 46, and have remained on stable NrtI therapy for the preceding 48 weeks.”
> “Blips were defined as transiently quantifiable HBV DNA (≥LLOQ) or detected HBsAg at a single visit.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.3-6"></a>

###### Criteria to restart nucleos(t)ide analogue therapy after cessation

> “Protocol-defined criteria to restart NrtI therapy included HBV DNA >20,000 IU/mL at a single visit, HBV DNA >2,000 IU/mL at two sequential visits, confirmed HBeAg reversion, or clinical/hepatic decompensation.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.3-7"></a>

###### 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.”
> “Eligible patients discontinued NA therapy at 48 weeks.”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.2.3-8"></a>

###### Placebo control, treatment arms, and data monitoring committee in the EU Clinical Trials Register record

> “Therapeutic confirmatory (Phase III) Yes”
> “Placebo Yes”
> “Number of treatment arms in the trial 2”
> “Trial has a data monitoring committee Yes”

Source: [EU Clinical Trials Register 2022-002268-53](https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002268-53/BG)

<a id="topic-3.1.2.3-9"></a>

###### Design of both B-Well trials stated by the company

> “The B-Well 1 and B-Well 2 trials are global multi-centre, randomised, double-blind, placebo-controlled trials conducted in 29 countries.”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="heading-3.1.2.4"></a>

##### 3.1.2.4 Eligibility Criteria

<a id="topic-3.1.2.4-1"></a>

###### Key inclusion and exclusion criteria summarized in the prescribing information

> “All participants were aged ≥18 years, had documented chronic HBV infection for ≥6 months, were receiving stable NrtI therapy (defined as no changes due to loss of virologic control for ≥6 months before the start of the trial and no plans for changes over the duration of the trial), and had serum HBsAg >100 to ≤3,000 IU/mL at screening, HBV DNA <90 IU/mL, and ALT ≤2X the upper limit of normal.”
> “Participants could be either HBeAg-positive or HBeAg-negative at baseline.”
> “Participants were excluded from the trial if they had a history, suspicion, or evidence of cirrhosis; co-infection with HCV, HIV, or HDV; history or evidence of potential vasculitis; eGFR ≤60 mL/min/1.73m2; or platelet count <140 x 109/L.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.4-2"></a>

###### Population described in the primary publication

> “All the patients were receiving stable nucleoside or nucleotide analogue (NA) therapy and had an HBsAg level of more than 100 to 3000 IU per milliliter.”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.2.4-3"></a>

###### Inclusion criteria in the ClinicalTrials.gov record

> “Participants who have documented chronic HBV infection ≥6 months prior to screening and currently receiving stable NA therapy defined as no changes to their NA regimen from at least 6 months prior to Screening and with no planned changes to the stable regimen over the duration of the study.”
> “Plasma or serum HBsAg concentration >100 IU/mL, but no greater than ≤3000 IU/mL.”
> “Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.”
> “Alanine aminotransferase (ALT) ≤2 × upper limit of normal (ULN).”
> “Participants who are willing and able to cease their NA treatment in accordance with the protocol.”
> “Ages Eligible for Study 18 Years and older”
> “Accepts Healthy Volunteers No”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.4-4"></a>

###### Exclusion criteria: coinfection, cirrhosis, malignancy, vasculitis, and extrahepatic disorders in the ClinicalTrials.gov record

> “Co-infection with: a) Current history of Hepatitis C infection or participants that have been cured for <12 months at the time of screening b) Human immunodeficiency virus (HIV), c) Hepatitis D virus.”
> “History of or suspected liver cirrhosis and/or evidence of cirrhosis.”
> “Diagnosed or suspected hepatocellular carcinoma.”
> “History of malignancy within the past 5 years except for specific cancers that are cured by surgical resection (e.g., skin cancer).”
> “History of vasculitis or presence of symptoms and signs of potential vasculitis (e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause) or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).”
> “History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).”
> “History of alcohol or drug abuse/dependence.”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.4-5"></a>

###### Exclusion criteria: prior and concomitant therapy in the ClinicalTrials.gov record

> “Currently taking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (≤2 weeks) or topical/inhaled steroid use.”
> “Currently taking, or has taken within 12 months of Screening, any interferon containing therapy.”
> “Participants requiring anti coagulation therapies (e.g., warfarin, Factor Xa inhibitors) or anti-platelet agents (like clopidogrel or aspirin) unless treatment can safely be discontinued throughout duration of the study, by the discretion of the investigator.”
> “Prior treatment with any oligonucleotide or siRNA within 12 months prior to the first dosing day.”
> “Prior treatment with bepirovirsen.”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.4-6"></a>

###### Definition of cirrhosis for exclusion in the EU Clinical Trials Register record

> “History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by”
> “Both APRI >2 and FibroSure/FibroTest result >0.7”
> “If only 1 parameter (APRI or FibroSure/FibroTest) result is positive, a discussion with the Medical Monitor is required before inclusion in study is permitted”
> “Liver biopsy (i.e., Metavir Score F4)”
> “Liver stiffness >12 kPa”

Source: [EU Clinical Trials Register 2022-002268-53](https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002268-53/BG)

<a id="topic-3.1.2.4-7"></a>

###### Other exclusion criteria in the EU Clinical Trials Register record

> “Hepatitis D virus defined as HDV antibody positive”
> “Diagnosed or suspected hepatocellular carcinoma as evidenced by the following”
> “Alpha-fetoprotein concentration ≥200 ng/mL”
> “If the screening alpha fetoprotein concentration is ≥50 ng/mL and <200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomization.”
> “Fridericia’s QT correction formula (QTcF) ≥450 msec”
> “At least 18 years of age at the time of signing the informed consent”

Source: [EU Clinical Trials Register 2022-002268-53](https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002268-53/BG)

<a id="heading-3.1.2.5"></a>

##### 3.1.2.5 Treatment

<a id="topic-3.1.2.5-1"></a>

###### Hibsago or placebo dosing regimen with background nucleos(t)ide analogue therapy

> “Participants were randomized 2:1 to receive HIBSAGO for 24 weeks (300 mg, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24), or placebo, together with their background NrtI therapy.”
> “Each dose of HIBSAGO was administered as two 150 mg subcutaneous injections into the abdomen, thigh, and/or outer area of upper arms.”
> “From Week 25 to 48, participants continued to receive their NrtI therapy without HIBSAGO or placebo.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.5-2"></a>

###### Dose and duration in the primary publication

> “subcutaneous bepirovirsen (at a weekly dose of 300 mg) or placebo for 24 weeks”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.2.5-3"></a>

###### 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.” |

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.5-4"></a>

###### Treatment arms in the company pipeline appendix

> “Arm A: bepirovirsen for 24 weeks”
> “Arm B: placebo”

Source: [GSK FY2025 pipeline assets and clinical trials appendix (2026)](https://www.gsk.com/media/rs0mbgqw/fy-2025-pipeline-assets-and-clinical-trials-report.pdf)

<a id="topic-3.1.2.5-5"></a>

###### 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.” |

Source: [EU Clinical Trials Register 2022-002268-53](https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002268-53/BG)

<a id="heading-3.1.2.6"></a>

##### 3.1.2.6 Study Outcomes

<a id="heading-3.1.2.6.1"></a>

###### 3.1.2.6.1 Rationale for Using Functional Cure as the Primary Endpoint

<a id="topic-3.1.2.6.1-1"></a>

###### Registered primary outcome measure in the ClinicalTrials.gov record

> “Number of participants achieving functional cure (FC) with baseline HBsAg ≤3000 IU/mL”
> “The number of participants who achieved FC after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication will be reported.”
> “The FC for HBV is defined as Sustained suppression (24 weeks or longer) of HBV DNA < Lower limit of quantification (LLOQ) off all HBV treatment and HBsAg not detected with or without HBsAb after a finite duration of therapy.”
> “Up to 72 weeks”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.6.1-2"></a>

###### Registered secondary outcome measures in the ClinicalTrials.gov record

> “Number of participants achieving FC with baseline HBsAg ≤1000 IU/mL”
> “Number of participants achieving sustained suppression of HBV DNA (<LLOQ) with baseline HBsAg ≤3000 IU/mL”
> “Number of participants achieving sustained suppression of HBV DNA (<LLOQ) with baseline HBsAg ≤1000 IU/mL”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.6.1-3"></a>

###### Primary and secondary end points and time point in the EU Clinical Trials Register record

> “Functional cure for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg ≤3000IU/mL”
> “Functional cure for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg ≤1000IU/mL”
> “Sustained suppression of HBV DNA (<LLOQ) for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg ≤3000IU/mL”
> “Sustained suppression of HBV DNA (<LLOQ) for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg ≤1000 IU/mL”
> “Timepoint(s) of evaluation of this end point Week 72”

Source: [EU Clinical Trials Register 2022-002268-53](https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002268-53/BG)

<a id="topic-3.1.2.6.1-4"></a>

###### Primary and three key secondary endpoints assessed at week 72 in the prescribing information

> “At Week 72, twenty-four weeks after possible cessation of NrtI treatment in eligible participants and 48 weeks after the last HIBSAGO dose, the primary and three key secondary efficacy endpoints were assessed.”
> “The primary efficacy endpoint was sustained suppression of HBV DNA (<LLOQ) and HBsAg not detected (LOD = 0.05 IU/mL), with or without hepatitis B surface antibodies, at 24 weeks after discontinuation of all chronic HBV treatment in the absence of rescue medication in participants with baseline HBsAg ≤3,000 IU/mL.”
> “The first key secondary endpoint was assessed by applying the same criteria to participants with baseline HBsAg ≤1,000 IU/mL.”
> “The second key secondary efficacy endpoint was sustained suppression of HBV DNA (<LLOQ), at 24 weeks after discontinuation of all chronic HBV treatment in the absence of rescue medication in participants with baseline HBsAg ≤3,000 IU/mL.”
> “The third key secondary endpoint was assessed by applying the same criteria of sustained suppression of HBV DNA (<LLOQ) to participants with baseline HBsAg ≤1,000 IU/mL.”
> “Blips in the Week 72 analysis window were permitted for the primary and key secondary endpoint analyses.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.6.1-5"></a>

###### Functional cure definition and assay thresholds in the company release

> “Defined as HBsAg not detected (qualitative; < 0.05 IU/mL) and HBV DNA < LLOQ (< 20 IU/mL or target not detected)”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.2.6.1-6"></a>

###### 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.”
> “The primary outcome was a functional cure at week 72.”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.2.6.1-7"></a>

###### 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.”
> “Moreover, HBsAg seroclearance is easy to measure with standardized and widely available assays.”
> “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.”

Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/)

<a id="topic-3.1.2.6.1-8"></a>

###### 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.”
> “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.”

Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/)

<a id="topic-3.1.2.6.1-9"></a>

###### 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.”

Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/)

<a id="topic-3.1.2.6.1-10"></a>

###### Efficacy endpoints and add-on placebo-controlled design for finite therapy: FDA guidance

> “HBsAg loss is considered the best predictor of sustained remission off-treatment”
> “To evaluate the primary efficacy outcome of sustained HBV DNA suppression off-treatment with HBsAg loss”
> “who are virally suppressed on NrtIs, sponsors can consider an add-on superiority trial against placebo with a current NrtI treatment regimen as the background therapy.”
> “It is expected that few subjects would meet such criteria on the placebo arm.”
> “For CHB, HBV DNA suppression with or without HBsAg loss is considered a validated surrogate endpoint that has been demonstrated to predict clinical outcomes”

Source: [FDA guidance on chronic hepatitis B drug development (2022)](https://www.fda.gov/media/117977/download)

<a id="topic-3.1.2.6.1-11"></a>

###### Functional cure as the primary endpoint of phase II/III trials: EASL clinical practice guideline

> “While the ultimate goal of treatment and the primary endpoint for phase II/III trials of finite treatments for chronic HBV infection is a "functional" cure, defined as sustained HBsAg loss (at least 24 weeks off therapy) with HBV DNA below the limit of quantification (LOQ), a sustained HBsAg level <100 IU/ml with HBV DNA <LOQ at 24 weeks off therapy is now being proposed as an alternative intermediate endpoint, or "partial cure".”
> “HBsAg loss is the ultimate goal of therapy.”

Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018)

<a id="topic-3.1.2.6.1-12"></a>

###### 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”
> “Functional cure is rare (≤ 5%) with NA therapy”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="heading-3.1.2.7"></a>

##### 3.1.2.7 Statistical Analysis Description

<a id="heading-3.1.2.7.1"></a>

###### 3.1.2.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.2.7.1-1"></a>

###### Planned number of participants in the EU Clinical Trials Register record

> “In the EEA 191”
> “In the whole clinical trial 900”
> “Number of subjects for this age range: 738”
> “Number of subjects for this age range: 162”

Source: [EU Clinical Trials Register 2022-002268-53](https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-002268-53/BG)

<a id="topic-3.1.2.7.1-2"></a>

###### Actual enrollment in the ClinicalTrials.gov record

> “Enrollment (Actual) 857”

Source: [ClinicalTrials.gov NCT05630820](https://clinicaltrials.gov/study/NCT05630820)

<a id="topic-3.1.2.7.1-3"></a>

###### Subjects in the company pipeline appendix

> “NCT05630820 - B-WELL 2 Phase III Patient Non-cirrhotic nucleos(t)ide analogue treated patients with chronic hepatitis B virus Subjects 857”

Source: [GSK FY2025 pipeline assets and clinical trials appendix (2026)](https://www.gsk.com/media/rs0mbgqw/fy-2025-pipeline-assets-and-clinical-trials-report.pdf)

<a id="topic-3.1.2.7.1-4"></a>

###### Randomized participants and full analysis set in the prescribing information

> “In Trial B-Well 2, a total of 857 participants were randomized (2:1) to receive either HIBSAGO or placebo.”
> “In the FAS of 856 participants who received at least one dose of HIBSAGO or placebo”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.7.1-5"></a>

###### Participants analyzed for the primary and first key secondary endpoints by treatment group

| Analysis population | Hibsago (n/N) | Placebo (n/N) |
| --- | --- | --- |
| Baseline HBsAg up to 3,000 IU/mL (primary endpoint) | “106/570” | “0/286” |
| Baseline HBsAg up to 1,000 IU/mL (first key secondary endpoint) | “95/342” | “0/179” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.7.1-6"></a>

###### Participants analyzed for the primary endpoint in the primary publication

> “in the B-Well 2 trial (in 106 of 570 patients [19%] vs. none of 286 patients)”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.2.7.1-7"></a>

###### Pooled B-Well 1 and B-Well 2 results: participants in both trials

> “evaluating bepirovirsen, an investigational antisense oligonucleotide (ASO) for the treatment of chronic hepatitis B (CHB) in over 1,800 patients from 29 countries.”

Source: [GSK press release, B-Well topline (2026)](https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-results-from-b-well-1-and-b-well-2-phase-iii-trials-for-bepirovirsen-a-potential-first-in-class-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.2.7.1-8"></a>

###### Pooled B-Well 1 and B-Well 2 results: participants in the pooled safety population

> “The safety of HIBSAGO in the treatment of chronic HBV infection has been evaluated in two pooled, Phase 3, placebo-controlled randomized trials (B-Well 1 and B-Well 2) in which 1,223 participants received at least one dose of HIBSAGO (300 mg subcutaneously, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24) and 611 participants received matching placebo.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.2.7.2"></a>

###### 3.1.2.7.2 Description of Analysis Sets

<a id="topic-3.1.2.7.2-1"></a>

###### Full analysis set used for efficacy

> “In the FAS of 856 participants who received at least one dose of HIBSAGO or placebo”
> “Not Detected at 24 Weeks after Cessation of NrtI Treatment (FAS Population)”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.7.2-2"></a>

###### Statistical methods for the primary endpoint: stratified common rate difference and exact Cochran-Mantel-Haenszel test

> “Common rate difference, calculated as a weighted average of the stratum-specific rate differences, with the associated 95% confidence interval (CI) from stratified Miettinen-Nurminen method.”
> “Based on two-sided p-value (exact Cochran-Mantel Haenszel).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.7.2-3"></a>

###### Statistical methods for the key secondary endpoints in participants with baseline HBsAg up to 1,000 IU/mL

> “95% Miettinen-Nurminen confidence interval (CI).”
> “Based on two-sided p-value (Boschloo's test).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.7.2-4"></a>

###### Ranked order of the primary and key secondary endpoints

> “A key ranked secondary endpoint evaluated functional cure in participants with baseline HBsAg ≤1000 IU/ml.”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.2.7.2-5"></a>

###### Pooled B-Well 1 and B-Well 2 results: pooled safety data set, weeks 1 to 36

> “The incidence of adverse reactions in the pooled safety data set (Weeks 1-36) with HIBSAGO is shown in Table 4.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.7.2-6"></a>

###### Pooled B-Well 1 and B-Well 2 results: subgroup analyses of the pooled population

> “Figure 1. Subgroup Analyses of Sustained Suppression of HBV DNA and HBsAg Not Detected at 24 Weeks after Cessation of NrtI Treatment, by Selected Baseline Factors (Pooled Population from B-Well 1 and B-Well 2).”
> “Overall: results are based on pooled data; Rate Difference: common rate difference (Miettinen-Nurminen method)”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.7.2-7"></a>

###### Pooled B-Well 1 and B-Well 2 results: post hoc analysis of predictors of nonresponse

> “A post-hoc exploratory analysis was conducted using the pooled data from B-Well 1 and B-Well 2 trials to determine predictors associated with nonresponse to treatment.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.7.2-8"></a>

###### Pooled B-Well 1 and B-Well 2 results: durability population of participants who stopped nucleos(t)ide analogue therapy

> “HIBSAGO recipients who met the criteria to discontinue NrtI therapy and discontinued NrtI therapy at Week 48 (295/1,220 across both trials) were monitored for an additional 48 weeks with assessments at Week 72 to assess the primary endpoint and Week 96 to evaluate the long-term durability of response (sustained HBV DNA <LLOQ and HBsAg not detected [LOD = 0.05 IU/mL] off all HBV treatment).”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

Additional sources: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="heading-3.1.2.8"></a>

##### 3.1.2.8 Results

<a id="heading-3.1.2.8.1"></a>

###### 3.1.2.8.1 Participant Disposition

<a id="topic-3.1.2.8.1-1"></a>

###### Randomized participants and full analysis set

> “In Trial B-Well 2, a total of 857 participants were randomized (2:1) to receive either HIBSAGO or placebo.”
> “In the FAS of 856 participants who received at least one dose of HIBSAGO or placebo”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

Additional sources: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="heading-3.1.2.8.2"></a>

###### 3.1.2.8.2 Baseline Characteristics

<a id="topic-3.1.2.8.2-1"></a>

###### Demographics: sex, age, race, and ethnicity

> “72% were male; the mean age was 49 years (range: 22 to 79 years); 68% were Asian, 27% were White, 4% were Black or African American, and 1% were Other; 5% were Hispanic or Latino”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.2-2"></a>

###### Geographic region of enrollment

> “59% were in Asia, 27% were in Europe, 6% were in US and Canada, 4% were in Latin America, and 4% were in Oceania”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.2-3"></a>

###### Baseline HBsAg level and HBV genotype

> “61% had HBsAg at baseline ≤1,000 IU/mL; 32% were genotype C, 25% were genotype B, 25% were genotype D, 11% were genotype A, 5% were other genotypes, 2% had unknown genotype”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.2-4"></a>

###### Baseline ALT and HBeAg status

> “93% had ALT ≤ULN at baseline; 92% were HBeAg negative at baseline”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.2-5"></a>

###### Time since chronic hepatitis B diagnosis

> “42% had been diagnosed with CHB for 20 years or longer, 32% for 10 to 20 years, 16% for 5 to 10 years, and 11% were diagnosed less than 5 years ago.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.2-6"></a>

###### Balance between treatment groups

> “In each trial, demographic characteristics were generally balanced between HIBSAGO and placebo participants.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

Additional sources: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="heading-3.1.2.8.3"></a>

###### 3.1.2.8.3 Efficacy Results

<a id="topic-3.1.2.8.3-1"></a>

###### Primary and key secondary endpoints met

> “Within both trials, the primary and key secondary endpoints were met.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.3-2"></a>

###### 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” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

> “and in the B-Well 2 trial (in 106 of 570 patients [19%] vs. none of 286 patients)”

Source: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.2.8.3-3"></a>

###### 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” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.3-4"></a>

###### 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” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.3-5"></a>

###### 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” |

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

<a id="topic-3.1.2.8.3-6"></a>

###### 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)” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.2.8.4"></a>

###### 3.1.2.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.2.8.5"></a>

###### 3.1.2.8.5 Safety Results

<a id="topic-3.1.2.8.5-1"></a>

###### Safety data reported as pooled B-Well 1 and B-Well 2 results

> “The safety of HIBSAGO in the treatment of chronic HBV infection has been evaluated in two pooled, Phase 3, placebo-controlled randomized trials (B-Well 1 and B-Well 2)”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.8.5-2"></a>

###### Most frequently observed adverse events

> “The trials showed an acceptable safety and tolerability profile consistent with other studies of bepirovirsen. The three most frequently observed adverse events were injection site erythema, local pain and temporary rise in the blood level of a liver enzyme.”

Source: [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

Additional sources: [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="heading-3.1.2.9"></a>

##### 3.1.2.9 Study Limitations

<a id="topic-3.1.2.9-1"></a>

###### 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.

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF); [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/)

<a id="topic-3.1.2.9-2"></a>

###### Small number of participants aged 75 years and older

> “Differences in efficacy in this age group versus younger adult patients cannot be determined due to the small number of participants.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.9-3"></a>

###### Exclusion of moderate or severe renal impairment

> “The clinical trials excluded participants with moderate or severe renal impairment (eGFR ≤60 mL/min/1.73m2) or uACR >0.3 mg/mg; insufficient data are available on the safety of HIBSAGO in these populations”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.9-4"></a>

###### No data in hepatitis D virus coinfection or on transmission

> “There are no data on the safety and efficacy of HIBSAGO in patients with HBV and hepatitis D virus (HDV) coinfection.”
> “There are no data on the effect of HIBSAGO in preventing transmission of HBV.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.2.9-5"></a>

###### Unknown clinical impact of binding-site variants with reduced susceptibility

> “The clinical impact of reduced susceptibility to HIBSAGO in these variants is unknown.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

Additional sources: [Lok (2026)](https://pubmed.ncbi.nlm.nih.gov/42206569/); [Hou et al. (2026b)](https://pubmed.ncbi.nlm.nih.gov/42777251/); [Pirzada et al. (2026)](https://pubmed.ncbi.nlm.nih.gov/42832798/); [Lens (2026)](https://pubmed.ncbi.nlm.nih.gov/42480667/)

<a id="heading-3.1.3"></a>

#### 3.1.3 B-Clear

<a id="heading-3.1.3.1"></a>

##### 3.1.3.1 Objective

<a id="topic-3.1.3.1-1"></a>

###### Aim stated in the primary publication

> “We conducted a phase 2b trial (B-Clear) to investigate the efficacy and safety of 12- and 24-week bepirovirsen treatment in participants with chronic HBV infection either receiving stable NA therapy or not receiving NA therapy.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.1-2"></a>

###### 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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.1-3"></a>

###### Objective stated in the ClinicalTrials.gov record

> “This study is intended to evaluate if treatment with GSK3228836 can achieve sustained virologic response (SVR), that is hepatitis B virus surface antigen (HBsAg) less than (<) lower limit of quantitation (LLOQ) and HBV deoxyribonucleic acid (DNA) <LLOQ sustained for 24 weeks post-GSK3228836 treatment end. In addition, the study will also evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of GSK3228836 in the 4 dosing regimens.”
> “This study will assess the efficacy and safety of treatment with GSK3228836 in two populations of participants with CHB; participants on stable nucleos(t)ide treatment (Cohort 1) and participants who are not currently on nucleos(t)ide therapy (Cohort 2).”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.1-4"></a>

###### Primary objective in the protocol

> “Efficacy: To assess the efficacy of the three dosing regimens of GSK3228836 in participants with CHB”

Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)

<a id="topic-3.1.3.1-5"></a>

###### Aim stated in the company release of results

> “The B-Clear phase IIb trial investigated the efficacy and safety of 12 or 24 weeks of treatment with bepirovirsen in people with CHB on stable NA treatment or not-on-NA treatment at study start.”

Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)

<a id="heading-3.1.3.2"></a>

##### 3.1.3.2 Location and Study Date

<a id="topic-3.1.3.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.2-2"></a>

###### Number of locations in the ClinicalTrials.gov record

> “This study has 121 locations”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.2-3"></a>

###### Trial dates, sites, and countries in the primary publication

> “B-Clear was a phase 2b, randomized, parallel-cohort trial conducted from July 27, 2020, to March 18, 2022, at 123 sites in 22 countries”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.2-4"></a>

###### 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.”
> “The study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) and the last patient visit occurred in March 2022.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.2-5"></a>

###### Presentation of end-of-study results

> “The end of study results will be presented today at the American Association for the Study of Liver Diseases’ Liver Meeting 2022 (AASLD) in Washington DC, and simultaneously published in the New England Journal of Medicine.”

Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)

<a id="heading-3.1.3.3"></a>

##### 3.1.3.3 Study Design

<a id="topic-3.1.3.3-1"></a>

###### Phase 2b, randomized, investigator-unblinded parallel-cohort design

> “We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy.”
> “The trial sponsor and participants were unaware of the trial-group assignments, which were known to the investigators. Randomization was performed with the use of an interactive Web-response system, with stratification according to hepatitis B e antigen (HBeAg) status (positive or negative) and baseline HBsAg level (≤3 or >3 log10 IU per milliliter).”
> “Participants were followed for up to 55 weeks, with a 24-week treatment period and a 24-week follow-up period. Participants receiving NA therapy continued such therapy during the trial.”
> “An independent data monitoring committee reviewed unblinded data.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.3-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.3-3"></a>

###### 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).”
> “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).”
> “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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.3-4"></a>

###### 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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.3-5"></a>

###### 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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.3-6"></a>

###### Rationale for unblinding site staff in the protocol

> “A partial blind study (participant and sponsor blinded, site staff unblinded) was chosen because there is a high probability that the PI and site staff could infer treatment assignment due to:”
> “Differences in the injection force due to the viscosity of GSK3228836 versus placebo saline.”
> “The comparisons/assessments for the placebo-first arm are not statistically powered.”

Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)

<a id="topic-3.1.3.3-7"></a>

###### Protocol amendment 2: nucleos(t)ide analogue initiation during suspected flares

> “The primary driver for this amendment was a request from a regulatory agency to include nucleos(t)ide analogue (NA) therapy initiation until hepatitis B flare could be ruled out (specifically for the patients who are not receiving NA therapy at baseline).”

Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)

<a id="heading-3.1.3.4"></a>

##### 3.1.3.4 Eligibility Criteria

<a id="topic-3.1.3.4-1"></a>

###### Key eligibility criteria in the primary publication

> “Participants were 18 years of age or older with documented chronic HBV infection for at least 6 months and an HBsAg level of more than 100 IU per milliliter. Participants who were receiving NA therapy were on a stable NA regimen and had an HBV DNA level of less than 90 IU per milliliter and an alanine aminotransferase (ALT) level less than or equal to 2 times the upper limit of the normal range. Participants who were not receiving NA therapy had never received such therapy or had ended NA therapy at least 6 months before screening and had an HBV DNA level of more than 2000 IU per milliliter and an ALT level of less than 3 times the upper limit of the normal range.”
> “Key exclusion criteria were the presence of hepatitis C, human immunodeficiency, or hepatitis D virus infection; cirrhosis; hepatocellular carcinoma; and interferon-containing therapy within 12 months before screening”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.4-2"></a>

###### 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.”
> “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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.4-3"></a>

###### Inclusion criteria in the ClinicalTrials.gov record: HBsAg, HBV DNA, and ALT

> “Plasma or serum HBsAg concentration >100 international units per milliliter (IU/mL).”
> “Plasma or serum HBV DNA concentration: Participants not currently on nucleos(t)ide analogue therapy, plasma or serum HBV DNA >2000 IU/mL; Participants who are receiving stable nucleos(t)ide analogue therapy must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.”
> “ALT for treatment naive participants and for participants who are not currently receiving treatment: ALT <3 times ULN will be included initially if agreed by the independent data monitoring committee (IDMC) after review of safety data, the ALT inclusion criteria may be expanded to include participants with ALT <5 times ULN; ALT less than equal to (<=2) times ULN for participants who are receiving stable nucleos(t)ide analogue therapy.”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.4-4"></a>

###### Exclusion criteria in the ClinicalTrials.gov record: coinfection, cirrhosis, and hepatocellular carcinoma

> “Co-infection with Current or past history of Hepatitis C virus (HCV), Human immunodeficiency virus (HIV), Hepatitis D virus (HDV).”
> “History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7.”
> “Regardless of APRI of Fibrosure/FibroTest score, if the participant meets one of the following criteria, they will be excluded from the study: Liver biopsy (i.e., Metavir Score F4); Liver stiffness >12 kilopascals (kPa).”
> “Diagnosed or suspected hepatocellular carcinoma as evidenced by the following: Alpha-fetoprotein concentration >=200 nanogram per milliliter (ng/mL)”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.4-5"></a>

###### Exclusion criteria in the ClinicalTrials.gov record: vasculitis, immune conditions, and prior therapy

> “History of vasculitis or presence of symptoms and signs of potential vasculitis (e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause) or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).”
> “History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).”
> “Currently taking, or took within 12 months of screening, any interferon-containing therapy.”
> “Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa inhibitors or anti-platelet agents like clopidogrel).”
> “Prior treatment with any oligonucleotide or small interfering ribonucleic acid (RNA) (Small interfering RNA [siRNA]) within 12 months prior to the first dosing day.”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.4-6"></a>

###### Exclusion criteria in the ClinicalTrials.gov record: laboratory values and QTc

> “Fridericia's QT correction formula (QTcF) >=450 milliseconds (msec)”
> “Laboratory results as follows: Serum albumin <3.5 grams per deciliter (g/dL), Glomerular filtration rate (GFR) <60 milliliter per minute per 1.73 square meter (mL/min /1.73 m^2) as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula”
> “International normalized ratio (INR) >1.25. Platelet count <140 times 10^9 cells/L, Total bilirubin >1.25 times ULN.”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.4-7"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="heading-3.1.3.5"></a>

##### 3.1.3.5 Treatment

<a id="topic-3.1.3.5-1"></a>

###### Four regimens randomized 3:3:3:1

> “Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4)”
> “Loading doses of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) were administered on days 4 and 11.”
> “Doses were administered once weekly as two subcutaneous injections (two syringes total; one syringe contained either bepirovirsen at a dose of 150 mg or placebo).”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.5-2"></a>

###### 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.”
> “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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.5-3"></a>

###### 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.”
> “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.”
> “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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.5-4"></a>

###### Study drug formulation in the ClinicalTrials.gov record

> “GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.”
> “Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.5-5"></a>

###### Rationale for the loading doses and the step-down regimen in the protocol

> “The loading schedule (i.e., loading doses) in Week 1 (Day 4) and Week 2 (Day 11) were included in order to accelerate the achievement of steady state concentration in the liver to increase the likelihood of observing anti-HBV activity during a short treatment duration.”
> “Study 209668 will also explore the impact on efficacy and safety of decreasing overall exposure to GSK3228836 by administrating a step-down dose of 150 mg GSK3228836 for 12 weeks after an initial 12 weeks of 300 mg GSK3228836 dose.”

Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)

<a id="heading-3.1.3.6"></a>

##### 3.1.3.6 Study Outcomes

<a id="heading-3.1.3.6.1"></a>

###### 3.1.3.6.1 Rationale for Using Sustained HBsAg and HBV DNA Loss as the Primary Endpoint

<a id="topic-3.1.3.6.1-1"></a>

###### Primary outcome definition and its purpose in the primary publication

> “To assess durability of response, the primary efficacy outcome was HBsAg and HBV DNA loss for 24 weeks after the discontinuation of bepirovirsen treatment in the absence of newly initiated antiviral treatment.”
> “The primary composite efficacy outcome was an HBsAg level below the lower limit of detection (0.05 IU per milliliter) and an HBV DNA level below the lower limit of quantification (20 IU per milliliter) maintained for 24 weeks after the planned end of bepirovirsen treatment in the absence of any medication initiated for the purpose of suppressing HBV replication (groups 1, 2, and 3)”
> “Group 4 (placebo-first group) was included to allow evaluation of the effect of a loading dose and evaluation of safety in the first 12 weeks, but the trial was not powered to assess the primary outcome in this group.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.6.1-2"></a>

###### Functional cure as the goal of therapy and its rarity with nucleos(t)ide analogues

> “The goal of therapy is to achieve functional cure”
> “fewer than 5% of patients have HBsAg loss after 12 months of treatment”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.6.1-3"></a>

###### 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.”
> “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].”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.6.1-4"></a>

###### 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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.6.1-5"></a>

###### 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.”
> “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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.6.1-6"></a>

###### Clinically meaningful sustained virologic response with a finite course: protocol

> “The proposed Phase 2b study (209668) will evaluate whether up to 24 weeks treatment with GSK3228836 results in a clinically meaningful rate of sustained virologic response (SVR, HBsAg <LLOQ and HBV DNA <LLOQ) with a finite course of GSK3228836.”
> “Taken together, the data suggest that a longer duration of GSK3228836 therapy may be required to both increase the rate of seroclearance and to achieve sustained seroclearance.”

Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)

<a id="topic-3.1.3.6.1-7"></a>

###### Primary outcome measure in the ClinicalTrials.gov record

| Field | Registry value |
| --- | --- |
| Outcome measure | “Number of Participants Achieving Sustained Virologic Response (SVR)” |
| Measure description | “The SVR was a composite endpoint defined as Hepatitis B surface antigen (HBsAg) and Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) levels were less than (<) Lower limit of quantitation (LLOQ) at the planned end of GSK3228836 treatment which is sustained for 24 weeks post-GSK3228836 treatment in the absence of rescue medication.” |
| Time frame | “Up to Week 48” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)

<a id="topic-3.1.3.6.1-8"></a>

###### Modified primary outcome permitting blips

> “An additional prespecified analysis used a modified version of the primary outcome that permitted “blips” (single-time-point increases in the HBsAg level to greater than or equal to the lower limit of detection or in the HBV DNA level to greater than or equal to the lower limit of quantification) in the response”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.6.1-9"></a>

###### Secondary efficacy and safety outcomes

> “Secondary efficacy outcomes included the difference between groups 1 and 2, groups 1 and 3, and groups 2 and 3 in the proportion of participants having a primary-outcome event; the proportion of participants having an HBsAg level below the lower limit of detection and an HBV DNA level below the lower limit of quantification at the end of treatment; log changes from baseline in HBsAg and HBV DNA levels (according to category of HBsAg or HBV DNA level); actual values and change from baseline in HBsAg, HBV DNA, HBeAg, and anti-HBs levels; and ALT normalization (ALT level less than or equal to the upper limit of the normal range) in the absence of newly initiated antiviral treatment in participants with an ALT level above the upper limit of the normal range at baseline.”
> “Increases in ALT levels, as well as class effects of antisense oligonucleotides (renal injury, injection-site reactions, thrombocytopenia, and vascular inflammation and complement activation), were evaluated as adverse events of special interest”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="heading-3.1.3.7"></a>

##### 3.1.3.7 Statistical Analysis Description

<a id="heading-3.1.3.7.1"></a>

###### 3.1.3.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.3.7.1-1"></a>

###### Planned sample size and its Bayesian basis

> “We planned to enroll approximately 440 participants: approximately 66 participants receiving NA therapy and 66 not receiving NA therapy in each of groups 1, 2, and 3 and approximately 22 participants receiving NA therapy and 22 not receiving NA therapy in group 4. This sample size was chosen on the basis of a Bayesian model and selected to provide at least a 75% posterior probability of the true response rate exceeding a fixed threshold under a range of assumed values for the threshold of interest and true response rate”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.7.1-2"></a>

###### 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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.7.1-3"></a>

###### Prior distribution in the protocol sample size determination

> “It is assumed that the number of responders follows a Binomial distribution, with a weakly informative prior (Beta (0.5, 0.5)) for the true response rate.”

Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)

<a id="topic-3.1.3.7.1-4"></a>

###### Participants analyzed in the primary publication

> “The intention-to-treat population included 457 participants (227 receiving NA therapy and 230 not receiving NA therapy)”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.7.1-5"></a>

###### Enrollment in the ClinicalTrials.gov record

> “A total of 457 participants were enrolled in the study. These 457 participants were from 2 different set of populations (referred here after as on nucleos(t)ide [NA] and not on NA therapy). Participants from these subpopulations were randomized in a ratio of 3:3:3:1 into 4 treatment arms for each population (total of 8 arms).”
> “The safety population was comprised of 455 participants, 2 participants excluded from arms GSK3228836 300mg for 12 weeks in both on NA and not on NA therapy population, respectively.”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="heading-3.1.3.7.2"></a>

###### 3.1.3.7.2 Description of Analysis Sets

<a id="topic-3.1.3.7.2-1"></a>

###### Efficacy and safety populations in the primary publication

> “Efficacy analyses were conducted in the intention-to-treat population, which included all randomly assigned participants, on the basis of the trial-group assignment. Safety analyses were conducted in all the participants who had undergone randomization and received at least one dose of bepirovirsen or placebo and were based on the trial agent received. As prespecified, analyses of all outcomes were conducted separately for participants receiving NA therapy and those not receiving NA therapy.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.7.2-2"></a>

###### Analysis sets defined in the statistical analysis plan

| Analysis set | Definition |
| --- | --- |
| Enrolled | “All participants who passed screening and entered the study.” |
| Intention-to-treat | “All randomized participants” |
| Safety | “All participants who received at least one dose of study treatment.” |
| Pharmacokinetic | “All participants in the Safety population who received an active study treatment and had at least 1 non-missing PK assessment” |
| Pharmacodynamic | “All participants in the Safety population for whom a Pharmacodynamic sample was obtained and analysed.” |

Source: [GSK 209668 statistical analysis plan (2022)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/SAP_001.pdf)

<a id="topic-3.1.3.7.2-3"></a>

###### Primary estimand and handling of intercurrent events

> “The primary estimand was the proportion of participants in groups 1, 2, and 3 who had a primary-outcome event, regardless of completion of treatment, interruptions in treatment, or adherence to treatment had they not been affected by wide disruptive events (e.g., the coronavirus disease 2019 pandemic).”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.7.2-4"></a>

###### Intercurrent event strategies in the protocol

> “The use of rescue medication has been incorporated into the definition of variable (composite strategy). Discontinuation of, interruption of, and adherence to IP will be ignored (treatment policy).”

Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)

<a id="topic-3.1.3.7.2-5"></a>

###### Estimation approach and Bayesian model

> “An estimation approach with no hypothesis testing was used to analyze the primary outcome. A Bayesian hierarchical model (including baseline stratification factors) was used to calculate the point estimate of the primary outcome and 95% credible interval. If the Bayesian hierarchical model did not converge, a post hoc unstratified Bayesian analysis was performed”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.7.2-6"></a>

###### Cohorts analyzed separately without multiplicity adjustment

> “All analyses were conducted separately for the two populations (On-NA and Not-on-NA). No adjustments were made for multiplicity.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.7.2-7"></a>

###### Analysis populations in the ClinicalTrials.gov results

> “The analysis was performed on the Intent to Treat (ITT) Set that includes all randomized participants who received a treatment randomization number. This population was based on the treatment the participant was randomized to. The analysis was conducted separately for the on NA treatment and not currently on NA treatment populations.”
> “The safety population included participants who received at least one dose of study treatment.”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="heading-3.1.3.8"></a>

##### 3.1.3.8 Results

<a id="heading-3.1.3.8.1"></a>

###### 3.1.3.8.1 Participant Disposition

<a id="topic-3.1.3.8.1-1"></a>

###### Discontinuation of the trial agent

> “13 participants (6%) receiving NA therapy and 23 (10%) not receiving NA therapy prematurely discontinued bepirovirsen or placebo, of whom 5 participants (2%) and 8 (3%), respectively, discontinued owing to adverse events”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.1-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="topic-3.1.3.8.1-3"></a>

###### Randomized participants who received no study treatment

> “Both participants did not receive study treatment, one due to randomization error (on NA therapy) and other due to the participant decision due to concern of potential side effects (not on NA therapy).”

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="heading-3.1.3.8.2"></a>

###### 3.1.3.8.2 Baseline Characteristics

<a id="topic-3.1.3.8.2-1"></a>

###### Demographic and clinical characteristics at baseline: intention-to-treat population, means ± SD

| Characteristic | 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) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age, years | “49.0±11.5” | “46.1±12.6” | “47.4±11.2” | “49.8±11.2” | “44.5±11.1” | “43.8±9.9” | “40.7±11.1” | “42.4±12.0” |
| Male sex, no. (%) | “48 (71)” | “49 (72)” | “51 (75)” | “17 (74)” | “33 (47)” | “41 (60)” | “39 (57)” | “11 (46)” |
| Body-mass index | “24.66±4.07” | “24.30±4.14” | “24.92±2.90” | “23.67±2.48” | “25.25±4.77” | “25.26±4.30” | “24.52±3.65” | “23.70±4.42” |
| Asian, no. (%) | “36 (53)” | “35 (51)” | “36 (53)” | “12 (52)” | “37 (53)” | “44 (65)” | “38 (56)” | “12 (50)” |
| White, no. (%) | “30 (44)” | “32 (47)” | “26 (38)” | “11 (48)” | “24 (34)” | “20 (29)” | “24 (35)” | “11 (46)” |
| Black, no. (%) | “2 (3)” | “1 (1)” | “4 (6)” | “0” | “9 (13)” | “4 (6)” | “6 (9)” | “1 (4)” |
| ALT at or below ULN, no. (%) | “62 (91)” | “60 (90)” | “62 (91)” | “21 (91)” | “50 (71)” | “48 (71)” | “47 (69)” | “15 (62)” |
| HBsAg 3 log10 IU/ml or less, no. (%) | “19 (28)” | “23 (34)” | “19 (28)” | “3 (13)” | “12 (17)” | “15 (22)” | “11 (16)” | “5 (21)” |
| HBsAg, log10 IU/ml | “3.29±0.62” | “3.26±0.61” | “3.33±0.59” | “3.43±0.43” | “3.72±0.77” | “3.65±0.72” | “3.66±0.67” | “3.76±0.79” |
| HBV DNA, log10 IU/ml | “0.48±0.64” | “0.39±0.60” | “0.55±0.66” | “0.40±0.62” | “5.02±1.53” | “5.14±1.56” | “5.57±1.65” | “5.00±1.55” |
| Negative HBeAg status, no. (%) | “50 (74)” | “47 (70)” | “44 (65)” | “16 (70)” | “49 (70)” | “52 (76)” | “52 (76)” | “17 (71)” |

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.2-2"></a>

###### 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” |

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.2-3"></a>

###### Comparability of trial groups and upper limit of normal for ALT

> “The demographic and clinical characteristics of the participants at baseline were similar across trial groups (Table 1).”
> “The upper limit of the normal range (ULN) for alanine aminotransferase (ALT) is 40 IU per liter for men and 33 IU per liter for women.”
> “Data were missing for 1 participant in group 2 who was receiving NA therapy, so the denominator is 67 rather than 68.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="heading-3.1.3.8.3"></a>

###### 3.1.3.8.3 Efficacy Results

<a id="topic-3.1.3.8.3-1"></a>

###### 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)” |

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.3-2"></a>

###### Primary outcome in the text of the primary publication

> “In group 1, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) receiving NA therapy and in 7 (10%; 95% credible interval, 0 to 38) not receiving NA therapy. In group 2, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 43) receiving NA therapy and in 4 (6%; 95% credible interval, 0 to 25) not receiving NA therapy. In group 3, a primary-outcome event occurred in 2 participants (3%; 95% credible interval, 0 to 16) receiving NA therapy and in 1 (1%; post hoc credible interval, 0 to 6) not receiving NA therapy”
> “Shown are point estimates and credible intervals from post hoc unstratified Bayesian analysis owing to nonconvergence of the prespecified stratified Bayesian hierarchical model.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.3-3"></a>

###### Modified primary outcome permitting blips: group 1

> “When we used the modified primary-outcome definition that allowed for “blips” (single-time-point increases in the HBsAg level to greater than or equal to the lower limit of detection or in the HBV DNA level to greater than or equal to the lower limit of quantification) in response, in group 1, a total of 7 participants (10%; 95% credible interval, 0 to 36) receiving NA therapy and 10 (14%; 95% credible interval, 0 to 64) not receiving NA therapy had a response.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.3-4"></a>

###### Primary outcome by baseline HBsAg level: group 1

> “In group 1, a total of 16% of the participants receiving NA therapy and 25% of those not receiving NA therapy with a low HBsAg level (≤3 log10 IU per milliliter) at baseline had a primary-outcome event, as compared with 6% and 7% of participants, respectively, with a high HBsAg level (>3 log10 IU per milliliter) at baseline (Fig. S3).”
> “A receiver-operating-characteristic analysis in group 1 indicated that an HBsAg level of approximately 3000 IU per milliliter (3.5 log10 IU per milliliter) at baseline may be an appropriate cutoff point for predicting response (Fig. S4). At the cutoff point of 3000 IU or less per milliliter in group 1, a total of 5 of 43 participants (12%) receiving NA therapy and 6 of 24 (25%) not receiving NA therapy had a primary-outcome event.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.3-5"></a>

###### Primary outcome by baseline HBeAg status: group 1

> “Among HBeAg-negative participants, a primary-outcome event occurred in those receiving NA therapy and in those not receiving NA therapy (in group 1, 10% of participants receiving NA therapy and 14% of those not receiving NA therapy). Among HBeAg-positive participants, a primary-outcome event occurred only in those receiving NA therapy (in group 1, 6% of participants receiving NA therapy and 0% of those not receiving NA therapy)”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.3-6"></a>

###### HBsAg levels at the end of treatment and 24 weeks after: group 1

> “In group 1, 43 participants (63%) receiving NA therapy and 41 (59%) not receiving NA therapy had an HBsAg level of less than 100 IU per milliliter by the end of treatment; the values were 26 (38%) and 20 (29%), respectively, at 24 weeks after the end of treatment (Figure 2).”
> “By the end of treatment in group 1, a total of 18 participants (26%) receiving NA therapy and 20 (29%) not receiving NA therapy had an HBsAg level below the lower limit of detection; at 24 weeks after the end of treatment, the values were 8 (12%) and 10 (14%), respectively”
> “In group 1, a total of 34 participants (50%) receiving NA therapy and 35 (50%) not receiving NA therapy had a decrease of at least 3 log10 IU per milliliter in the HBsAg level at the end of treatment; the incidence of relapse at the end of the trial was lowest in group 1 (Fig. S11).”
> “For many participants, HBsAg and HBV DNA levels increased after treatment discontinuation (Figs. S7 and S8).”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.3-7"></a>

###### HBV DNA below the lower limit of quantification: participants not receiving NA therapy

> “Among participants not receiving NA therapy, the number in group 1 who had an HBV DNA level below the lower limit of quantification was 26 (37%) at the end of treatment and 19 (27%) at 24 weeks after the end of treatment, as compared with 20 (29%) and 15 (22%), respectively, in group 2; 18 (26%) and 9 (13%), respectively, in group 3; and 4 (17%) at both time points in group 4.”
> “Among participants in group 1 not receiving NA therapy, a decrease of at least 3 log10 IU per milliliter in the HBV DNA level was observed in 27 participants (39%) at the end of treatment and in 18 (26%) at 24 weeks after the end of treatment (Fig. S12).”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.3-8"></a>

###### HBeAg loss, seroconversion, and anti-HBs

> “Of the participants who were positive for HBeAg and negative for antibodies against hepatitis B e (anti-HBe) at baseline, 10 of 63 (16%) receiving NA therapy and 8 of 41 (20%) not receiving NA therapy had HBeAg loss at 24 weeks after the end of treatment; 7 participants (11%) receiving NA therapy and 8 (20%) not receiving NA therapy had seroconversion (HBeAg loss and positivity for anti-HBe). Of the participants who had a primary-outcome event, 7 (50%) receiving NA therapy and 6 (50%) not receiving NA therapy had anti-HBs at the end of the trial.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.3-9"></a>

###### 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%” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="topic-3.1.3.8.3-10"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="topic-3.1.3.8.3-11"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="topic-3.1.3.8.3-12"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="topic-3.1.3.8.3-13"></a>

###### Primary outcome and low-baseline-HBsAg subgroup in the company release

> “Bepirovirsen, with a loading dose at day 4 and 11, and at a dose of 300mg per week for 24 weeks (treatment arm 1) resulted in 9% of patients on-NA and 10% of patients not-on-NA achieving the primary outcome of HBsAg levels below the Lower Limit of Detection (LLOD) and HBV DNA levels below the Lower Limit of Quantification (LLOQ). Patients with low baseline hepatitis B surface antigen levels3 responded best to treatment with bepirovirsen in treatment arm 1 with 16% of patients on-NA and 25% of patients not-on-NA achieving the primary outcome.”
> “Prospectively defined as including patients with a baseline HBsAg ≤ 1000 IU/mL”

Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)

Additional sources: [Bouquet et al. (2026)](https://doi.org/10.1016/j.jhep.2025.12.025)

<a id="heading-3.1.3.8.4"></a>

###### 3.1.3.8.4 Health-related Quality of Life and Patient-reported Outcomes

<a id="topic-3.1.3.8.4-1"></a>

###### Patient-reported outcome objective and instruments planned in the protocol

> “Patient Reported Outcomes: To assess changes from baseline in patient reported outcomes following 12 weeks, 12 weeks + 12 weeks step-down, and 24 weeks of treatment with GSK3228836.”
> “Change from baseline of HBQOL and EQ-5D.”
> “The HBQOL has been designed to assess quality of life in patients with Hepatitis B. It consists of 31 items and 6 domains: psychological well-being, anticipation anxiety, vitality, stigma, transmissibility and vulnerability.”

Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)

<a id="topic-3.1.3.8.4-2"></a>

###### Patient-reported outcome results

No evidence found.

<a id="heading-3.1.3.8.5"></a>

###### 3.1.3.8.5 Safety Results

<a id="topic-3.1.3.8.5-1"></a>

###### Safety summary by group and cohort: safety population, number of participants (percent)

| Adverse event | On NA, group 1 (N=68) | On NA, group 2 (N=67) | 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=67) | Not on NA, group 3 (N=68) | Not on NA, group 4 (N=24) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Weeks 1 to 12: any adverse event | “53 (78)” | “57 (85)” | “52 (76)” | “10 (43)” | “63 (90)” | “55 (82)” | “59 (87)” | “13 (54)” |
| Weeks 1 to 12: any grade 3 or 4 adverse event | “5 (7)” | “9 (13)” | “5 (7)” | “0” | “10 (14)” | “9 (13)” | “7 (10)” | “0” |
| Weeks 1 to 12: any serious adverse event | “1 (1)” | “1 (1)” | “3 (4)” | “0” | “3 (4)” | “0” | “0” | “0” |
| Weeks 1 to 12: injection-site reaction | “38 (56)” | “47 (70)” | “43 (63)” | “3 (13)” | “50 (71)” | “41 (61)” | “46 (68)” | “3 (12)” |
| Weeks 1 to 12: vascular inflammation and complement activation | “24 (35)” | “31 (46)” | “30 (44)” | “1 (4)” | “45 (64)” | “38 (57)” | “42 (62)” | “6 (25)” |
| Weeks 1 to 12: thrombocytopenia | “12 (18)” | “9 (13)” | “11 (16)” | “3 (13)” | “21 (30)” | “17 (25)” | “19 (28)” | “4 (17)” |
| Weeks 1 to 12: increased ALT level | “7 (10)” | “10 (15)” | “6 (9)” | “0” | “15 (21)” | “12 (18)” | “11 (16)” | “1 (4)” |
| Weeks 1 to 12: renal injury | “2 (3)” | “6 (9)” | “6 (9)” | “0” | “5 (7)” | “3 (4)” | “9 (13)” | “1 (4)” |
| All visits: any adverse event | “56 (82)” | “59 (88)” | “53 (78)” | “16 (70)” | “65 (93)” | “60 (90)” | “62 (91)” | “19 (79)” |
| All visits: adverse event leading to discontinuation of trial agent | “2 (3)” | “3 (4)” | “3 (4)” | “0” | “3 (4)” | “1 (1)” | “5 (7)” | “0” |
| All visits: any grade 3 or 4 adverse event | “7 (10)” | “11 (16)” | “8 (12)” | “0” | “16 (23)” | “15 (22)” | “13 (19)” | “4 (17)” |
| All visits: any serious adverse event | “1 (1)” | “1 (1)” | “4 (6)” | “0” | “6 (9)” | “2 (3)” | “3 (4)” | “0” |
| All visits: injection-site reaction | “41 (60)” | “49 (73)” | “43 (63)” | “11 (48)” | “52 (74)” | “41 (61)” | “49 (72)” | “12 (50)” |
| All visits: vascular inflammation and complement activation | “30 (44)” | “34 (51)” | “31 (46)” | “10 (43)” | “49 (70)” | “40 (60)” | “46 (68)” | “12 (50)” |
| All visits: thrombocytopenia | “19 (28)” | “16 (24)” | “12 (18)” | “6 (26)” | “32 (46)” | “21 (31)” | “21 (31)” | “6 (25)” |
| All visits: increased ALT level | “7 (10)” | “10 (15)” | “6 (9)” | “6 (26)” | “20 (29)” | “19 (28)” | “16 (24)” | “5 (21)” |
| All visits: renal injury | “4 (6)” | “9 (13)” | “6 (9)” | “2 (9)” | “7 (10)” | “6 (9)” | “9 (13)” | “3 (12)” |

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.5-2"></a>

###### Adverse events during weeks 1 through 12, when a placebo comparison was possible

> “During weeks 1 through 12, when comparison between bepirovirsen and placebo was possible, adverse events were more common during bepirovirsen treatment in groups 1, 2, and 3 (in 78%, 85%, and 76%, respectively, of participants receiving NA therapy and in 90%, 82%, and 87%, respectively, of those not receiving NA therapy) than during receipt of placebo in group 4 (in 43% of those receiving NA therapy and 54% of those not receiving NA therapy) (Table 3). For example, injection-site reactions, pyrexia, fatigue, and increased ALT levels were reported more frequently with bepirovirsen than with placebo (Tables S13 and S14).”
> “During weeks 1 through 12, no participants in group 4 (placebo) had serious adverse events; five participants receiving NA therapy (one in group 1, one in group 2, and three in group 3) and three participants not receiving NA therapy (all in group 1) had serious adverse events. Grade 3 or 4 adverse events occurred in 7 to 13% of participants receiving NA therapy and in 10 to 14% of those not receiving NA therapy in groups 1, 2, and 3, as compared with 0 in group 4.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.5-3"></a>

###### Adverse events during weeks 1 through 48

> “During weeks 1 through 48, the proportion of participants who reported adverse events was higher among those not receiving NA therapy than among those receiving NA therapy (Table 3), with a higher incidence of increased ALT level, increased aspartate aminotransferase level, decreased platelet count, decreased complement factor C3 level, and decreased complement factor C4 level (Tables S17 and S18). In patients receiving NA therapy and in those not receiving NA therapy, the most common adverse events were injection-site reactions (erythema, pain, and pruritus).”
> “Overall, 17 participants had adverse events leading to discontinuation of bepirovirsen or placebo, with 0 to 4% frequency among participants receiving NA therapy and 0 to 7% frequency among those not receiving NA therapy (Table 3).”
> “Grade 3 or 4 adverse events occurred in 74 participants overall, with 0 to 16% frequency among those receiving NA therapy and 17 to 23% frequency among those not receiving NA therapy. Serious adverse events were reported in 6 participants (3%) receiving NA therapy and 11 (5%) not receiving NA therapy; 1 serious adverse event in participants receiving NA therapy and 3 in those not receiving NA therapy were considered by the investigator to be related to bepirovirsen treatment (Table 3 and Tables S19 and S20). No deaths were reported.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.5-4"></a>

###### ALT increases of 3 times ULN or more

> “Overall, 39 of 225 participants receiving NA therapy (17%) and 93 of 227 not receiving NA therapy (41%) had a transient increase in the ALT level to at least 3 times the upper limit of the normal range between randomization and the end of follow-up (Table S6).”
> “There were two serious adverse events related to ALT changes, which are discussed further in the Results section in the Supplementary Appendix, and one case of Gilbert’s syndrome. Otherwise, increases in ALT levels were asymptomatic and resolved without increases in bilirubin or alkaline phosphatase levels and without evidence of liver dysfunction.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.5-5"></a>

###### Injection-site reactions leading to withdrawal

> “Overall, injection-site reactions were the most common adverse events; two participants (one receiving NA therapy and one not receiving NA therapy) withdrew owing to an injection-site reaction.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.8.5-6"></a>

###### 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%)” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="topic-3.1.3.8.5-7"></a>

###### Individual serious adverse events: ClinicalTrials.gov results

| Serious adverse 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 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Cryoglobulinaemia | “1/68 (1.47%)” | “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%)” |
| Hepatic function abnormal | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “1/70 (1.43%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Hepatitis B | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “1/70 (1.43%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Systemic inflammatory response syndrome | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “1/70 (1.43%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Hepatocellular carcinoma | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “1/68 (1.47%)” | “0/24 (0.00%)” |
| Bile duct cancer | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “1/70 (1.43%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Interstitial lung disease | “0/68 (0.00%)” | “0/67 (0.00%)” | “1/68 (1.47%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Cerebral infarction | “0/68 (0.00%)” | “0/67 (0.00%)” | “1/68 (1.47%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |

Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)

<a id="topic-3.1.3.8.5-8"></a>

###### Safety statement in the company release

> “There were no safety signals to preclude further development. AEs leading to treatment discontinuation occurred in 17 participants overall, with 0–4% frequency in participants on-NA, and 0–7% frequency in participants not-on-NA. Serious AEs (SAEs) were reported in 6 (3%) participants on-NA and 11 (5%) participants not-on-NA; 1 SAE in the on-NA and 3 in the not-on-NA population were considered related to treatment.”

Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)

<a id="heading-3.1.3.9"></a>

##### 3.1.3.9 Study Limitations

<a id="topic-3.1.3.9-1"></a>

###### 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.

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027); [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.9-2"></a>

###### 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”
> “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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.9-3"></a>

###### 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.”

Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)

<a id="topic-3.1.3.9-4"></a>

###### Authors' statements on the size of the effect and the need for larger trials

> “Although this is a relatively low percentage of participants overall, it indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both.”
> “Larger trials and longer follow-up are needed to assess the safety and efficacy of bepirovirsen.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.3.9-5"></a>

###### Sponsor role in design, analysis, and drafting

> “The sponsor, GSK, designed and oversaw the trial conduct and data collection and analysis. Professional writers paid by the sponsor prepared the first draft of the manuscript under the authors’ direction.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

Additional sources: [Hoofnagle (2022)](https://pubmed.ncbi.nlm.nih.gov/36346068/); [Vaillant (2023)](https://pubmed.ncbi.nlm.nih.gov/36947477/); [Yuen et al. (2023a)](https://pubmed.ncbi.nlm.nih.gov/36947478/); [Lens (2023)](https://pubmed.ncbi.nlm.nih.gov/36801391/); [Mak et al. (2023)](https://pubmed.ncbi.nlm.nih.gov/37902953/)

<a id="heading-3.1.4"></a>

#### 3.1.4 B-Sure

<a id="heading-3.1.4.1"></a>

##### 3.1.4.1 Objective

<a id="topic-3.1.4.1-1"></a>

###### Objective stated in the ClinicalTrials.gov record

> “This is a global multi-center, long-term follow-up study to assess durability of efficacy, as measured by maintenance of treatment response from the parent study, in participants who participated in a previous bepirovirsen study and achieved a complete or partial response.”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.1-2"></a>

###### Official title in the ClinicalTrials.gov record

> “A Prospective, Multi-Centre Study (B-Sure) to Evaluate Long-Term Durability of Treatment Response in Chronic Hepatitis B Participants With and Without Nucleos(t)Ide Therapy Who Have Participated in a Previous Bepirovirsen Treatment Study”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.1-3"></a>

###### Aim stated on the first annual report poster

> “B-Sure (NCT04954859) was initiated to generate long-term data on the durability of response in participants with a complete or partial response after bepirovirsen treatment and included an option for NA cessation for On-NA participants.”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.1-4"></a>

###### Durability follow-up described in the B-Clear publications

> “Durability of response is being investigated in the B-Sure trial (ClinicalTrials.gov number, NCT04954859), which will follow participants for an additional 33 months and includes criteria for stopping NA therapy.”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-3.1.4.1-5"></a>

###### Durability follow-up described in the company release of B-Clear results

> “Longer term durability of response will be investigated in the B-Sure trial which will follow participants for an additional 33 months and includes criteria for stopping NA therapy with the possibility to demonstrate functional cure in patients who successfully stop all medication and continue to demonstrate no serologic evidence of HBsAg or HBV DNA.”

Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)

<a id="heading-3.1.4.2"></a>

##### 3.1.4.2 Location and Study Date

<a id="topic-3.1.4.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.2-2"></a>

###### Number of locations in the ClinicalTrials.gov record

> “This study has 163 locations”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.2-3"></a>

###### Congress presentations of interim data

> “Presented at the European Association for the Study of the Liver (EASL) Congress, Vienna, Austria, 21–24 June 2023”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

> “EASL 2025 |   7–10 May 2025   |  Amsterdam, The Netherlands”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="heading-3.1.4.3"></a>

##### 3.1.4.3 Study Design

<a id="topic-3.1.4.3-1"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.3-2"></a>

###### Parent studies and participant categories

> “Eligible participants will be enrolled in this study after completing the end of study (EoS) visit in the respective parent bepirovirsen studies (studies B-Clear [209668: NCT04449029], B-Together [209348: NCT04676724], B-Fine [212602: NCT04544956], B-Well 1 [202009: NCT05630807], B-Well 2 [219288: NCT05630820], and TH HBV ASO-001 [217023: NCT05276297]). Participants will be categorized as Not-on-NA, NA-cessated, or On-NA based on their nucleos(t)ide analogue (NA) status in the parent study. No further treatment with bepirovirsen will be administered in this study.”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.3-3"></a>

###### Follow-up duration by arm

> “Participants will be followed up for 33 months. Participants maintaining either functional cure (FC) or a partial response off NA treatment at Month 33 will be eligible to be followed up for an additional 2 years.”
> “NA cessation will occur at 3 months in 206882 for eligible and willing participants.”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.3-4"></a>

###### Response categories and follow-up schedule: B-Clear responders

> “The B-Sure study recruited B-Clear study responders (CR or PR at the end of the B-Clear study) for long-term follow-up”
> “CR was defined as HBsAg and HBV DNA <LLOQ”
> “PR was defined as HBsAg <100 IU/mL and HBV DNA <LLOQ”
> “Following entry into B-Sure, Not-on-NA participants were followed up at Months 3, 9, 15, 21, 27 and 33 (Figure 1). This is the third data review, with a cut-off date of 9 September 2024”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="topic-3.1.4.3-5"></a>

###### Follow-up schedule after nucleos(t)ide analogue cessation: B-Clear On-NA responders

> “On-NA participants, if eligible, discontinued NAs 3 months after entry into B-Sure and were followed every 2 weeks in the first month after NA cessation, then every month in the next 3 months, and every 3 months up to Month 15. Subsequently, they were monitored every 6 months up to Month 33”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="topic-3.1.4.3-6"></a>

###### Durability assessment in the first annual report

> “The durability of the response was assessed as follows: Not-on-NA: Time from achieving complete response to loss of response; On-NA: Time from NA cessation to loss of complete response.”
> “Adverse events (AEs) were recorded at each visit to assess safety.”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="heading-3.1.4.4"></a>

##### 3.1.4.4 Eligibility Criteria

<a id="topic-3.1.4.4-1"></a>

###### General inclusion and exclusion criteria in the ClinicalTrials.gov record

> “Participants who enter the study on stable NA are willing and able to cease their NA treatment in accordance with the NA cessation schedule.”
> “Participants who have/or are currently participating in another non-GSK interventional clinical study exploring HBV treatment since completing their treatment with bepirovirsen.”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.4-2"></a>

###### Inclusion criteria for participants rolling over from B-Clear, B-Together, and B-Fine

> “Participants who have previously received at least one dose of bepirovirsen AND”
> “Achieved the PSPO in the parent study and who maintained a response until the End of Study (EoS) visit in their parent study (defined as complete responders to bepirovirsen from the parent study) OR”
> “Demonstrated hepatitis B virus surface antigen (HBsAg) reduction greater than or equal to (≥) 1.0 log10 international units per milliliter (IU/mL) from parent study Baseline with HBsAg levels less than (<) 100 IU/mL and HBV deoxyribonucleic acid (DNA) < lower limit of quantification (LLOQ) for 24 weeks after the actual end of treatment regimen, in the absence of rescue medication and maintained until their EoS visit in the parent study.”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.4-3"></a>

###### Inclusion criteria for participants rolling over from B-Well 1 and B-Well 2

> “NA cessated at Week 48 in parent study and achieved at least HBsAg <1 IU/ml and HBV DNA <LLOQ at the EOS visit (Week 96) in the parent study OR”
> “Achieved NA cessation criteria at Week 48 in parent study but have not stopped NA treatment, and are maintaining at least HBsAg <1 IU/ml and HBV DNA <LLOQ at EOS visit (Week 72) of parent study OR”
> “Did not achieve NA cessation criteria in parent study but achieved at least HBsAg <1 IU/ml and HBV DNA <LLOQ at EOS visit (Week 72) of parent study.”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.4-4"></a>

###### Criteria for nucleos(t)ide analogue discontinuation and restart: B-Clear On-NA responders

> “Participants could discontinue NA if they meet all of the following criteria: a) If a CR: achieve the B-Clear primary outcome and maintain a CR without reversion (HBsAg ≥LLOQ or HBV DNA ≥LLOQ confirmed by 2 consecutive visits at 1 week [±3 days] apart) in the absence of rescue medication up to 3 months into B-Sure (excluding blips)”
> “b) have stable NA treatment for 3 months into B-Sure; c) have ALT <1.25xULN at 2.5 months into B-Sure.”
> “Participants could resume NA treatment if they meet any of the following criteria: a) HBV DNA >20000 IU/mL; b) HBV DNA >2000 IU/mL after 2 sequential lab results confirmed within 1 week (±3 days) from the date of first result (with or without ALT elevation)”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="topic-3.1.4.4-5"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="heading-3.1.4.5"></a>

##### 3.1.4.5 Treatment

<a id="topic-3.1.4.5-1"></a>

###### No study treatment administered

> “No study treatment will be administered in this study.”
> “No study drug will be administered in this study. Eligible participants who received prior treatment with bepirovirsen in the parent studies will be included.”
> “No study drug will be administered in this study. Eligible participants who received prior treatment with placebo in the parent studies (209668, 202009, and 219288) will be included to maintain the blind in the still ongoing parent studies.”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.5-2"></a>

###### Nucleos(t)ide analogue cessation 3 months after entry

> “On-NA participants, if eligible, will cease NA 3 months after entry into B-Sure and be followed more intensively.”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="heading-3.1.4.6"></a>

##### 3.1.4.6 Study Outcomes

<a id="heading-3.1.4.6.1"></a>

###### 3.1.4.6.1 Rationale for Using Durability of Functional Cure as the Primary Endpoint

<a id="topic-3.1.4.6.1-1"></a>

###### Primary outcome measures in the ClinicalTrials.gov record

| Primary outcome measure | Time frame |
| --- | --- |
| “Percentage of Not-on-NA participants without loss of parent study primary outcome (PSPO)” | “From primary endpoint assessment in the parent study up to Month 57” |
| “Percentage of On-NA participants rolling over from studies 209668 and 209348 without loss of functional cure (FC) after NA-cessation in study 206882” | “From Month 3 up to Month 57” |
| “Percentage of On-NA participants rolling over from study 217023 without loss of FC after NA-cessation in study 206882” | “From Month 3 up to Month 33” |
| “Percentage of NA-cessated participants rolling over from studies 202009 and 219288 without loss of FC after NA-cessation in the parent study” | “From primary endpoint assessment in the parent study up to Month 33” |

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.6.1-2"></a>

###### Functional cure as the optimal endpoint

> “is regarded as the optimal treatment endpoint for chronic HBV infection, but is rarely achieved with current standard-of-care NA therapies”
> “Functional cure, defined as sustained HBsAg loss and HBV DNA <LLOQ for 24 weeks off all treatment”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="topic-3.1.4.6.1-3"></a>

###### Time off treatment required before a response counts as functional cure: Not-on-NA participants

> “Participants maintaining a CR at Month 3 (i.e. at least 9 months off bepirovirsen, allowing for a 3-month washout period”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="topic-3.1.4.6.1-4"></a>

###### Time off treatment required before a response counts as functional cure: On-NA participants

> “Participants maintaining a CR at Month 9 (i.e. 6 months post NA cessation and 15–18 months off bepirovirsen) achieved functional cure”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="topic-3.1.4.6.1-5"></a>

###### Functional cure rarely achieved with nucleos(t)ide analogues: first annual report

> “Functional cure, defined as the loss of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA after treatment cessation,1,2 is rarely (<5%) achieved with current standard of care nucleos(t)ide analogue (NA) therapies.”
> “Red box: equivalent to functional cure, all Not-on-NA patients have at least 36 weeks off all treatment (allowing for bepirovirsen wash out), all On-NA participants have at least 24 weeks off NA therapy.”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.6.1-6"></a>

###### Secondary outcome measures: relapse, retreatment, and delayed functional cure

> “Percentage of On-NA and NA-cessated participants with PSPO in the parent study who have virologic relapse or use of any rescue medication after NA cessation (in either parent study or study 206682)”
> “Percentage of On-NA and NA-cessated participants with PSPO in the parent study who receive NA retreatment after NA cessation (in either parent study or study 206682)”
> “Percentage of Not-on-NA participants with a partial response in the parent study and a delayed FC in study 206882 in absence of rescue medication after end of treatment in the parent study”
> “Percentage of participants with mutations”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="heading-3.1.4.7"></a>

##### 3.1.4.7 Statistical Analysis Description

<a id="heading-3.1.4.7.1"></a>

###### 3.1.4.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.4.7.1-1"></a>

###### Planned enrollment in the ClinicalTrials.gov record

> “Enrollment (Estimated)”
> “360”

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="topic-3.1.4.7.1-2"></a>

###### B-Clear complete responders enrolled: first annual report

> “From B-Clear, 13/16 On-NA and 12/16 Not-on-NA complete responders enrolled into B-Sure.”
> “In the Phase 2b, randomised, B-Clear study (NCT04449029), 32 participants on and not on NA therapy (On-NA and Not-on-NA) achieved a complete response (modified primary endpoint: HBsAg <0.05 IU/mL and HBV DNA level <20 IU/mL [<lower limit of quantification; LLOQ]) maintained for 24 weeks after planned end of bepirovirsen treatment, in the absence of newly initiated antiviral treatment [rescue medication]).”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.7.1-3"></a>

###### B-Clear Not-on-NA responders enrolled: third report

> “From the B-Clear Not-on-NA participants, 11 CRs and 5 PRs enrolled into B-Sure (Table 1).”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="topic-3.1.4.7.1-4"></a>

###### B-Clear On-NA responders enrolled: third report

> “From the B-Clear On-NA participants, 14 CRs and 26 PRs enrolled into B-Sure”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="heading-3.1.4.7.2"></a>

###### 3.1.4.7.2 Description of Analysis Sets

<a id="topic-3.1.4.7.2-1"></a>

###### Complete responders by the modified primary outcome: first annual report

> “This analysis presents the first annual report from the B-Sure study in B-Clear complete responders (according to the modified primary outcome).”
> “Two participants each in the On-NA and Not-on-NA populations missed the primary endpoint but were included using the modified primary endpoint due to a HBsAg ‘blip’ during B-Clear.”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.7.2-2"></a>

###### Participants enrolled in error and excluded from the flow analysis: Not-on-NA

> “One non-responder from B-Clear was enrolled into B-Sure; this participant did not meet eligibility criteria but was enrolled in error”
> “One non-responder from B-Clear was enrolled into B-Sure in error and was excluded from the flow diagram”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="topic-3.1.4.7.2-3"></a>

###### Participants enrolled in error and reclassification after blips: On-NA

> “Four non-responders from B-Clear were enrolled into B-Sure; these participants did not meet eligibility criteria but were enrolled in error”
> “Further consideration of how to handle blips has led to the re-classification of individual participants at the end of the parent study, and therefore the data presented here are different than that previously shared within the abstract”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="heading-3.1.4.8"></a>

##### 3.1.4.8 Results

<a id="heading-3.1.4.8.1"></a>

###### 3.1.4.8.1 Participant Disposition

<a id="topic-3.1.4.8.1-1"></a>

###### Disposition of B-Clear On-NA complete responders: first annual report

> “69% (9/13) participants ceased NA as per protocol.”
> “8% (1/13) withdrew prior to NA cessation due to commitments”
> “23% (3/13) were not eligible to cease NA (2 did not meet protocol defined criteria for cessation due to detectable HBsAg and 1 due to investigator discretion despite HBsAg <0.05 IU/mL)”
> “Mean duration between B-Clear end-of-study and entry into B-Sure: 102 days (range 94–113).”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.8.1-2"></a>

###### Time from B-Clear end of study to B-Sure entry: Not-on-NA, first annual report

> “Mean duration between B-Clear end-of-study and entry into B-Sure: 84 days (range 0–105).”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.8.1-3"></a>

###### Disposition of B-Clear Not-on-NA responders: third report

> “As of the data cut-off date, these participants were continuing the trial”
> “Two PR participants started NA treatment after B-Sure enrolment”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="topic-3.1.4.8.1-4"></a>

###### Disposition of B-Clear On-NA responders: third report

> “As of the data cut-off date, 38/40 (95%) participants were continuing the trial”
> “Of the 14 CRs, 10 (71%) discontinued NAs 3 months into B-Sure”
> “Of the 26 PRs, 22 (85%) discontinued NAs 3 months after rollover into B-Sure”
> “Due to safety, HBsAg reversion, and/or investigator error”
> “Due to safety of participant and/or investigator discretion based on lab results”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="heading-3.1.4.8.2"></a>

###### 3.1.4.8.2 Baseline Characteristics

<a id="topic-3.1.4.8.2-1"></a>

###### 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)” |

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.8.2-2"></a>

###### 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)” |

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="topic-3.1.4.8.2-3"></a>

###### 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)” |

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="heading-3.1.4.8.3"></a>

###### 3.1.4.8.3 Efficacy Results

<a id="topic-3.1.4.8.3-1"></a>

###### Durability in B-Clear Not-on-NA responders: third report

> “Of the 11 CR participants, 8 (73%) maintained a CR at Month 3, thus achieving functional cure (Figure 2). All 8 participants maintained functional cure at 21 months of B-Sure”
> “All 6 participants with Month 27 data (i.e. 33–36 months off-bepirovirsen) had maintained functional cure at this timepoint”
> “For PR participants, 1/5 maintained a PR at 3 months; this response was maintained to Month 27 of B-Sure (Figure 2)”
> “One participant subsequently had seroclearance by Month 15 (Figure 3)”
> “Only 6 of the 8 CRs had reached the 27-month follow-up timepoint at the data cut”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="topic-3.1.4.8.3-2"></a>

###### Durability in B-Clear On-NA responders after nucleos(t)ide analogue cessation: third report

> “Of the 14 CRs, 10 (71%) discontinued NAs 3 months into B-Sure; of these, 8 (80%) achieved functional cure 6 months post NA cessation and all 8 maintained functional cure up to 18 months”
> “Of the 2 participants who did not achieve functional cure at 6 months post NA cessation, 1 had restarted NA therapy by 24 months post NA cessation”
> “Of the 26 PRs, 22 (85%) discontinued NAs 3 months after rollover into B-Sure; of these, 2 (9%) achieved functional cure and were maintaining functional cure for up to 18 months. Five out of 22 (23%) maintained PR status at 6 months post NA cessation; of these, 2 maintained to 24 months post NA cessation; the 3 losses of PR were due to HBV DNA reversion”
> “Among 22 PRs who discontinued NAs, 13 had restarted NA therapy by 24 months post NA cessation”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="topic-3.1.4.8.3-3"></a>

###### Durability in B-Clear complete responders: first annual report

> “Of the 9 participants with ≥3 months of follow-up within B-Sure, 78% (7/9) maintained response (Figure 2). No participant met NA restart criteria.”
> “Of the 3 participants with ≥9 months of follow-up within B-Sure, 100% (3/3) maintained response (≥15–18 months after end of bepirovirsen).”
> “Of the 7 participants who ceased NA and had ≥6 months of follow-up within B-Sure, 86% (6/7) maintained response 3 months post NA cessation (Figure 3).”
> “Of the 4 participants who ceased NA and had ≥9 months of follow-up within B-Sure, 100% (4/4) maintained response 6 months post NA cessation; no participants restarted NAs.”
> “In this global, long-term, follow-up study, 7 participants (n=4 On-NA and n=3 Not-on-NA) demonstrated HBsAg and HBV DNA loss 15–18 months post bepirovirsen cessation.”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.8.3-4"></a>

###### Sub-analysis of B-Together responders announced for AASLD 2025 (no figures released)

> “Phase II B-Sure study sub-analysis shows durability of functional cure in chronic hepatitis B (CHB) patients treated with bepirovirsen and pegylated interferon (Peg-IFN)”
> “Data will be presented from a sub-analysis from the B-Sure phase II study, evaluating the achievement and duration of a functional cure in CHB patients who responded to treatment with bepirovirsen followed by Peg-IFN, a type of immune-boosting therapy.”

Source: [GSK press release, AASLD 2025 (2025)](https://www.gsk.com/en-gb/media/press-releases/gsk-presents-data-from-its-advancing-liver-pipeline-at-aasld-2025/)

<a id="heading-3.1.4.8.4"></a>

###### 3.1.4.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.4.8.5"></a>

###### 3.1.4.8.5 Safety Results

<a id="topic-3.1.4.8.5-1"></a>

###### Adverse events in B-Clear complete responders: first annual report

| n (%) | On-NA (N=13) | Not-on-NA (N=12) |
| --- | --- | --- |
| Any adverse events | “6 (46)” | “2 (17)” |
| Mild | “5 (38)” | “0” |
| Moderate | “1 (8)” | “2 (17)” |
| Adverse events related to previous treatment in B-Clear | “0” | “0” |
| Any serious adverse events | “0” | “0” |

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.8.5-2"></a>

###### No latent adverse drug effect: first annual report

> “There were no safety signals that suggested a latent adverse drug effect following use of bepirovirsen (Table 2).”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.8.5-3"></a>

###### ALT increases after nucleos(t)ide analogue cessation: B-Clear On-NA responders, third report

> “After stopping bepirovirsen, there were no safety signals that suggested a latent adverse drug effect following use of bepirovirsen”
> “AEs of increased ALT were reported in 1 (2%) participant pre-NA cessation (mild severity) and 3 (7%) participants post NA cessation (2 mild, 1 moderate severity)”
> “Of the 34 participants who discontinued NAs, 5 had ALT ≥2 × ULN”
> “One participant who restarted NA therapy had ALT >5 × ULN; no other participants had ALT >5 × ULN”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="topic-3.1.4.8.5-4"></a>

###### Safety in B-Clear Not-on-NA responders: third report

> “After stopping bepirovirsen, there were no safety signals that suggested a latent adverse drug effect following treatment with bepirovirsen”

Source: [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf)

<a id="heading-3.1.4.9"></a>

##### 3.1.4.9 Study Limitations

<a id="topic-3.1.4.9-1"></a>

###### 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.

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859); [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf); [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf); [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="topic-3.1.4.9-2"></a>

###### Small numbers stated by the authors of the first annual report

> “These data provide early evidence on the durability of response observed with bepirovirsen, although they should be interpreted with caution due to low participant numbers. The B-Sure study will continue to evaluate the durability of bepirovirsen response up to 33 months and data will be published when available.”

Source: [Gadano et al. (2023)](https://www.postersessiononline.eu/173580348_eu/congresos/ILC2023/aula/-LBP_15_ILC2023.pdf)

<a id="topic-3.1.4.9-3"></a>

###### Benefit in partial responders not yet established

> “Clinical benefits (i.e. reduced HBsAg and HBV DNA) were particularly evident in participants who achieved a CR in the parent study. The potential benefits in participants with a PR are being further analysed”

Source: [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf)

<a id="topic-3.1.4.9-4"></a>

###### Open-label, non-randomized design in the ClinicalTrials.gov record

| Field | Registry value |
| --- | --- |
| Allocation | “Non-Randomized” |
| Masking | “None (Open Label)” |
| Results | “No Results Posted” |

Source: [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859)

<a id="heading-3.1.5"></a>

#### 3.1.5 B-Together

<a id="heading-3.1.5.1"></a>

##### 3.1.5.1 Objective

<a id="topic-3.1.5.1-1"></a>

###### Primary aim: whether sequential bepirovirsen and Peg-IFN reduces relapse and improves response

> “The B-Together study investigated if sequential bepirovirsen and pegylated interferon-α-2a (Peg-IFN) therapy can reduce relapse rates and improve response rates.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.1-2"></a>

###### Hypothesis: conversion of partial responders and prevention of relapse

> “The B-Together study was designed as a proof-of-concept study based on the hypothesis that Peg-IFN sequential therapy could increase response rates by converting bepirovirsen partial responders (those who had a reduction in HBsAg levels but were HBsAg > lower limit of quantification [LLOQ; 0.05 IU/ml] at EoT) to full responders on Peg-IFN treatment and/or by preventing relapse.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.1-3"></a>

###### Objective as registered

> “This study is intended to evaluate if 12 or 24 weeks of treatment with GSK3228836 followed by up to 24 weeks of pegylated interferon (PegIFN) can increase the rate of hepatitis B virus surface antigen (HBsAg) loss in participants on stable nucleos(t)ide analogue (NA) therapy, and whether virologic response can be sustained once PegIFN treatment is discontinued.”

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="topic-3.1.5.1-4"></a>

###### Questions the protocol was designed to answer

> “Does sequential therapy with GSK3228836 (12 or 24 weeks) followed by up to 24 weeks of PegIFN result in improved rates of efficacy in NA-controlled CHB patients compared to GSK3228836 monotherapy?”
> “Is the efficacy rate affected by the duration of treatment with GSK3228836 prior to starting PegIFN?”

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="topic-3.1.5.1-5"></a>

###### Secondary and exploratory objectives

> “Secondary objectives included efficacy of bepirovirsen and Peg-IFN sequential therapy on HBV biomarkers (HBsAg and HBeAg) and virus-specific antibody responses (anti-HBeAg status, anti-HBs), durability of virological response, and between-treatment comparison for the primary outcome.”
> “Exploratory objectives included generating serum proteomic profiles of enrolled participants (supplementary methods).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.1-6"></a>

###### Objective of the post hoc biomarker analysis

> “We investigated bepirovirsen’s MoA in relation to virological response, hepatocyte death, and ALT increases.”

Source: [Joshi et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12923464/)

<a id="heading-3.1.5.2"></a>

##### 3.1.5.2 Location and Study Date

<a id="topic-3.1.5.2-1"></a>

###### Trial period, sites, and countries

> “The trial was conducted from 28 January 2021–17 February 2023 at 52 sites in 11 countries (Table S1).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.2-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="topic-3.1.5.2-3"></a>

###### Regulatory identifiers

> “EudraCT: 2020-002979-35”
> “IND: IND 122685”

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="topic-3.1.5.2-4"></a>

###### Overlap of sites with B-Clear

> “73.5% of the sites from B-Clear are the same as those in B-Together”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="heading-3.1.5.3"></a>

##### 3.1.5.3 Study Design

<a id="topic-3.1.5.3-1"></a>

###### Phase IIb, multicentre, randomised, open-label design

> “B-Together was a phase IIb, multicentre, randomised, open-label trial to assess the efficacy and safety of sequential treatment with bepirovirsen followed by Peg-IFN in participants with chronic HBV infection.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.3-2"></a>

###### Randomisation, stratification, and allocation concealment

> “Participants were randomised 1:1 to treatment Arm 1 or 2 (Fig. 1). Treatment arms were stratified by HBsAg level (HBsAg ≤1,000/>1,000 IU/ml) and hepatitis B e antigen (HBeAg) status (positive [+]/negative [−]). Investigators and participants were unblinded to study intervention throughout the trial. To protect against foreknowledge of pre-randomisation, allocation was concealed by central blocking.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.3-3"></a>

###### Treatment windows and off-treatment follow-up

> “Participants received weekly bepirovirsen 300 mg (plus a loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks (bepirovirsen treatment window) followed by weekly Peg-IFN 180 μg for up to 24 weeks (Peg-IFN treatment window), if eligible. Participants were followed for an additional 24 (Arm 1) or 36 (Arm 2) weeks (off-treatment) following planned end of Peg-IFN treatment. Participants continued NA treatment throughout the trial.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.3-4"></a>

###### Oversight

> “The sponsor, GSK, was involved in the design, conduct, and analysis of the trial. An Independent Data Monitoring Committee reviewed ongoing unblinded safety data.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.3-5"></a>

###### 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.” |

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="topic-3.1.5.3-6"></a>

###### Rationale for sequential therapy

> “Lower levels of baseline HBsAg consistently predict the highest response rate to PegIFN in terms of HBsAg loss [Ren, 2019].”

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="topic-3.1.5.3-7"></a>

###### Rationale for enrolling participants controlled on NA therapy

> “Although we believe these flares to be therapeutic in nature and related to immune clearance of HBV from the liver, our intention is to manage the risk of possible exacerbations of hepatitis by first evaluating proof of concept (POC) in participants whose infection is already under control with stable NA therapy.”

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="heading-3.1.5.4"></a>

##### 3.1.5.4 Eligibility Criteria

<a id="topic-3.1.5.4-1"></a>

###### Key inclusion and exclusion criteria

> “B-Together enrolled adult participants with confirmed chronic HBV infection (were HBsAg positive [+]) for ≥6 months before screening and currently receiving stable NA therapy (defined as no changes to their NA regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study) except telbivudine. Key inclusion criteria were: eligible for Peg-IFN treatment with plasma or serum HBsAg >100 IU/ml (measured using Roche Elecsys HBsAg II quant II), HBV DNA <90 IU/ml, and alanine aminotransferase (ALT) ≤2x the upper limit of normal (ULN). Key exclusion criteria were: HCV, HDV, or HIV co-infection; cirrhosis; hepatocellular carcinoma; vasculitis.”
> “Peg-IFN eligibility was assessed at screening and bepirovirsen EoT.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.4-2"></a>

###### Age range and registered inclusion criteria

> “18 to 75 years of age at the time of signing the informed consent.”
> “Participants who are eligible to be treated with PegIFN.”
> “Plasma or serum HBsAg concentration >100 International Units per milliliter (IU/mL).”
> “Plasma or serum HBV DNA concentration <90 IU/mL.”

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="topic-3.1.5.4-3"></a>

###### Cirrhosis exclusion

> “History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by both: Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7.”
> “Regardless of APRI of Fibrosure/FibroTest score, if the participant meets one of the following criteria, they will be excluded from the study: a) Liver biopsy (i.e., Metavir Score F4); b) Liver stiffness >12 kilopascals (kPa).”

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="topic-3.1.5.4-4"></a>

###### Exclusions related to interferon, psychiatric history, and prior oligonucleotides

> “Pre-existing severe psychiatric condition or a history of severe psychiatric disorders, including severe depression, suicidal ideation and attempted suicide.”
> “Participants with prior treatment with PegINF or interferon will be excluded”
> “Prior treatment with any oligonucleotide or small interfering ribonucleic acid (siRNA) within 12 months prior to the first dosing day.”

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="topic-3.1.5.4-5"></a>

###### Laboratory exclusions

> “Laboratory results as follows: Serum albumin <3.5 grams per deciliter (g/dL); Glomerular filtration rate (GFR) <60 milliliter per minute per 1.73 square meter (mL/min /1.73 m^2) as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula (for Japan, Japanese Society of Nephrology Chronic Kidney Disease Initiative [JSN-CKDI equation]); International normalized ratio (INR) >1.25; Platelet count <140x10^9 cells/L; Baseline hemoglobin <10 g/dL; Total bilirubin >1.25 times ULN”

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="heading-3.1.5.5"></a>

##### 3.1.5.5 Treatment

<a id="topic-3.1.5.5-1"></a>

###### Bepirovirsen dose and duration followed by Peg-IFN

> “In this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300 mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180 μg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.5-2"></a>

###### Start of Peg-IFN after bepirovirsen

> “Eligible participants began Peg-IFN treatment 1 week after the last dose of bepirovirsen; those not immediately able to start Peg-IFN were re-assessed on Weeks 2, 3, 4, 6, 8, 10, and 13 of the Peg-IFN eligibility window. Participants who failed to meet Peg-IFN eligibility criteria did not start Peg-IFN treatment.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.5-3"></a>

###### Registered arms

| Arm | Quoted description |
| --- | --- |
| Arm 1 | “Participants on stable NA therapy received 300 milligrams per week (mg/week) GSK3228836 for 24 weeks (plus a loading dose on Day 4 and 11), followed by Pegylated Interferon (PegIFN) 180 microgram per week (mcg/week) up to 24 weeks.” |
| Arm 2 | “Participants on stable NA therapy received 300mg/week GSK3228836 for 12 weeks (plus a loading dose on Day 4 and 11), followed by PegIFN 180 mcg/week up to 24 weeks.” |
| Background therapy | “Participants will continue to receive their NA therapy for the duration of the study.” |

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="topic-3.1.5.5-4"></a>

###### Rationale for 24 weeks of Peg-IFN rather than 48 weeks

> “Current PegIFN treatment guidelines recommend 48 weeks treatment. In this study PegIFN will be administered for a maximum of 24 weeks duration.”
> “PegIFN administration is associated with numerous adverse effects and can be difficult to tolerate.”

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="topic-3.1.5.5-5"></a>

###### Rationale for 12 or 24 weeks of bepirovirsen

> “In the proposed study, we will investigate 2 different durations of treatment with GSK3228836 (12 and 24 weeks at 300 mg/week) prior to starting PegIFN in order to optimise rates of sustained seroclearance.”

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="heading-3.1.5.6"></a>

##### 3.1.5.6 Study Outcomes

<a id="heading-3.1.5.6.1"></a>

###### 3.1.5.6.1 Rationale for Using Sustained HBsAg and HBV DNA Loss 24 Weeks After Sequential Treatment as the Primary Endpoint

<a id="topic-3.1.5.6.1-1"></a>

###### Primary outcome definition

> “The primary efficacy outcome was the percentage of participants in each treatment arm who achieved HBsAg and HBV DNA levels below the LLOQ (HBsAg: 0.05 IU/ml, HBV DNA: 20 IU/ml) at every visit for 24 weeks after the planned end of sequential treatment, in the absence of newly initiated antiviral rescue therapy.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.6.1-2"></a>

###### Post hoc alternative primary outcome and definition of relapse

> “Post hoc analysis evaluated an alternative primary outcome definition assessing the proportion of participants in each arm with HBsAg and HBV DNA <LLOQ at 24 weeks post-EoT. Relapse was defined as any value of HBsAg or HBV DNA ≥LLOQ or newly initiated antiviral rescue therapy.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.6.1-3"></a>

###### Functional cure as the endpoint for new HBV therapies

> “Prognosis may be improved by achieving functional cure,2 defined as sustained loss of hepatitis B surface antigen (HBsAg) and unquantifiable HBV DNA 24 weeks following treatment cessation.”
> “Functional cure is uncommon (NA only: <3%, Peg-IFN only: <7%) with current treatments.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.6.1-4"></a>

###### Protocol rationale for sustained virologic response

> “The rationale for the proposed study is to evaluate the potential of up to 48 weeks of sequential therapy with GSK3228836 and PegIFN to achieve sustained loss of HBsAg and HBV DNA in participants on stable NA therapy. Sustained virologic response is defined as undetectable levels of HBsAg and HBV DNA on treatment and maintaining this for a minimum of 24 weeks off-treatment (GSK3228836 and PegIFN).”
> “Recently, a functional cure of CHB infection has been endorsed as the endpoint for new HBV therapies [Kim, 2018].”

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="topic-3.1.5.6.1-5"></a>

###### Registered primary outcome measure

> “Sustained virologic response is defined as undetectable levels of Hepatitis B surface antigen (HBsAg) and Hepatitis-B virus deoxy-ribonucleic acid (HBV DNA) on treatment. The SVR was a composite endpoint defined as HBsAg and HBV DNA levels were less than (<) Lower limit of quantitation (LLOQ) at the planned end of sequential treatment of GSK3228836 and PegIFN treatment which is sustained for 24 weeks post-GSK3228836 and PegIFN treatment in the absence of any rescue medication.”

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724)

<a id="topic-3.1.5.6.1-6"></a>

###### Safety outcomes and adverse events of special interest

> “AESIs were pre-defined as a group of MedDRA preferred terms (Table S3), allowing for a comprehensive review of safety data not limited to a specific preferred term, and included ALT increase, vascular inflammation and complement activation, renal injury, and thrombocytopenia for bepirovirsen, and ALT increase, hematologic events, and psychiatric events for Peg-IFN.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="heading-3.1.5.7"></a>

##### 3.1.5.7 Statistical Analysis Description

<a id="heading-3.1.5.7.1"></a>

###### 3.1.5.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.5.7.1-1"></a>

###### Planned enrollment and Bayesian sample size basis

> “The trial planned to enrol approximately 100 participants. Using Bayesian inference, this sample size was selected to provide a 65% posterior probability of the true response rate exceeding a fixed threshold under a range of assumed values for the threshold of interest and a range of assumed true response rates.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.7.1-2"></a>

###### Planned participants per arm in the protocol

> “For the entire study, approximately 100 participants will be enrolled and randomised to achieve approximately 50 participants in each treatment group”

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="topic-3.1.5.7.1-3"></a>

###### Participants enrolled and analyzed

> “The intent-to-treat population included 108 participants (Arm 1, n = 55; Arm 2, n = 53).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.7.1-4"></a>

###### Participants contributing to the biomarker analysis

> “This post hoc peripheral longitudinal biomarker exploratory analysis examined serum proteomics and whole blood transcriptomics from peripheral blood mononuclear cell samples from 82 participants.”

Source: [Joshi et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12923464/)

<a id="heading-3.1.5.7.2"></a>

###### 3.1.5.7.2 Description of Analysis Sets

<a id="topic-3.1.5.7.2-1"></a>

###### Efficacy and safety populations

> “Efficacy analyses were conducted on the intent-to-treat (ITT) population, which included all randomised participants, analysed based on treatment assignment. Safety analyses were conducted on all randomised participants who received ≥1 dose of study treatment, analysed based on treatment received.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.7.2-2"></a>

###### Primary analysis model and its simplification

> “Primary analysis was conducted when the last participant completed their Week 72 visit. Due to convergence issues caused by quasi-complete separation in the data, the planned Bayesian hierarchical model for the primary analysis was simplified to a Bayesian logistic regression model with fixed effects for treatment arm and baseline stratification factors.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.7.2-3"></a>

###### Handling of wide disruptive events such as COVID-19

> “For participants who experienced WDEs (e.g. COVID-19 infections or pandemic lockdowns) resulting in discontinuation or significant interruption/non-adherence to the investigational product (a gap of ≥21 days between treatment doses during the on-treatment period except for the Peg-IFN eligibility window), this model utilised multiple imputation (assuming missing at random) to assess the primary outcome.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.7.2-4"></a>

###### 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.” |

Source: [GSK 209348 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/24/NCT04676724/Prot_000.pdf)

<a id="topic-3.1.5.7.2-5"></a>

###### 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].”
> “Null responders were non-responders who did not have two or more consecutive visits with a > 0.4 log10 HBsAg reduction while on treatment.”

Source: [Joshi et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12923464/)

<a id="heading-3.1.5.8"></a>

##### 3.1.5.8 Results

<a id="heading-3.1.5.8.1"></a>

###### 3.1.5.8.1 Participant Disposition

<a id="topic-3.1.5.8.1-1"></a>

###### Withdrawals, Peg-IFN eligibility, and missed visits

> “Nine participants (Arm 1, n = 6; Arm 2, n = 3) withdrew from the study, two due to AEs (Fig. S1). All but two participants (one in each Arm) were eligible to begin Peg-IFN treatment following bepirovirsen treatment. COVID-19 infections and lockdowns resulted in missed treatment visits for nine participants (all in Arm 1).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.1-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724?tab=results)

<a id="topic-3.1.5.8.1-3"></a>

###### Treatment discontinuations for adverse events

> “Four participants permanently discontinued treatment due to an AE (1 dermatitis allergic and 2 injection-site reactions during bepirovirsen treatment; 1 depression during Peg-IFN treatment).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.1-4"></a>

###### Missed doses due to wide disruptive events

> “For nine participants in Arm 1, WDEs resulted in discontinuation of, significant interruption of, or non-adherence to the investigational product. Of these participants, two missed bepirovirsen dosing (2–4 missed visits) and seven missed Peg-IFN dosing (2–13 missed visits; Table S6).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="heading-3.1.5.8.2"></a>

###### 3.1.5.8.2 Baseline Characteristics

<a id="topic-3.1.5.8.2-1"></a>

###### Baseline HBsAg level and HBeAg status: most participants above 1,000 IU/ml and HBeAg negative

> “Baseline demographics and disease characteristics were similar between arms (Table 1).12 Baseline demographics were also similar to the B-Clear study (Table S4). Most participants had baseline HBsAg >1,000 IU/ml (n = 74 [69%]) and were HBeAg− (n = 80 [74%]).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.2-2"></a>

###### 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” |

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.2-3"></a>

###### Baseline immunological heterogeneity between arms

> “Higher expression of 148 proteins was seen in a subset of Arm 2 versus Arm 1 participants (Fig. S1a and S1b).”

Source: [Joshi et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12923464/)

<a id="heading-3.1.5.8.3"></a>

###### 3.1.5.8.3 Efficacy Results

<a id="topic-3.1.5.8.3-1"></a>

###### Primary outcome: 5 of 55 participants in Arm 1 and 8 of 53 in Arm 2

> “The primary outcome was achieved in 5 (9%) and 8 (15%) participants in Arm 1 and Arm 2, respectively. The resulting point estimates (95% credible interval) from the Bayesian model were 12% (0, 46%) for Arm 1 and 15% (0, 56%) for Arm 2 (Table 2). Seven (13%) participants in Arm 1 and 8 (15%) in Arm 2 achieved the alternative primary outcome (Table 2).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-2"></a>

###### 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” |

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-3"></a>

###### Registry primary outcome and between-arm comparison

| Measure | Arm 1 | Arm 2 |
| --- | --- | --- |
| Participants analyzed (ITT) | “55” | “53” |
| Percentage achieving SVR for 24 weeks off treatment | “9” | “15” |

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724?tab=results)

> “The point estimate for the difference in SVR and its respective credible interval (CI) were evaluated at 24 weeks off of planned treatment for both arms.”
> “-29 to 11”

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724?tab=results)

<a id="topic-3.1.5.8.3-4"></a>

###### Baseline HBsAg threshold among responders

> “All participants who met the primary outcome had baseline HBsAg ≤3,000 IU/ml.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-5"></a>

###### Predictors of response in the logistic regression model

> “The final model identified low baseline HBsAg level, high BMI, and treatment with tenofovir alafenamide fumarate or tenofovir disoproxil fumarate as statistically significant predictors of response (Table 3).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-6"></a>

###### 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” |

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-7"></a>

###### Response and relapse at the end of each treatment window

> “At bepirovirsen EoT, 20/55 (36%; Arm 1) and 12/53 (23%; Arm 2) participants achieved HBsAg and HBV DNA <LLOQ. Of these, 8/20 (40%; Arm 1) and 5/12 (42%; Arm 2) relapsed before Peg-IFN EoT. At Peg-IFN EoT, 13/55 (24%; Arm 1) and 9/53 (17%; Arm 2) participants had HBsAg and HBV DNA <LLOQ. Of these, 7/12 (58%; Arm 1) and 0/9 (0%; Arm 2) relapsed during follow-up.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-8"></a>

###### Peg-IFN did not convert partial responders

> “Only two participants in Arm 2 who did not achieve HBsAg and HBV DNA <LLOQ at bepirovirsen EoT had HBsAg and HBV DNA loss following Peg-IFN treatment.”
> “Both these participants were likely on their way to HBsAg and HBV DNA <LLOQ irrespective of Peg-IFN (Fig. S3).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-9"></a>

###### Indirect comparison of relapse with B-Clear

> “In B-Clear, 63% and 75% participants relapsed off-treatment after 24-week and 12-week bepirovirsen 300 mg treatment, respectively. Here, 58% (Arm 1) and 0% (Arm 2) of participants who achieved HBsAg and HBV DNA <LLOQ at Peg-IFN EoT relapsed off-treatment.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-10"></a>

###### Durability of primary outcome response in Arm 2

> “All but one participant in Arm 2 who achieved the primary outcome sustained HBsAg and HBV DNA <LLOQ until off-treatment Week 36.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-11"></a>

###### HBeAg loss and anti-HBe seroconversion

> “Of the participants who were HBeAg+ at baseline, 8/14 (57%) and 1/14 (7%) became anti-HBe+ by the end of the bepirovirsen treatment period in Arm 1 and Arm 2, respectively. At the end of the Peg-IFN treatment period, this changed to 5/9 (56%) and 1/9 (11%), respectively.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-12"></a>

###### Anti-HBs response

> “Among participants who achieved HBsAg and HBV DNA <LLOQ by Peg-IFN EoT, anti-HBs status did not correlate with primary outcome achievement; anti-HBs values were highly variable and overlapping in those who relapsed and those who maintained HBsAg <LLOQ (Fig. S8).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-13"></a>

###### ALT elevations by treatment window

> “Transient increases in ALT levels ≥3x ULN were seen in 38% of participants in Arm 1 and 40% in Arm 2; 24% and 19% of participants, respectively, experienced such increases during the bepirovirsen treatment window, and 18% and 25%, respectively, during the Peg-IFN treatment window. During the bepirovirsen treatment window, ALT increases coincided with a decline in HBsAg, whereas there was no association between HBsAg and ALT levels during the Peg-IFN treatment window (Fig. S9).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-14"></a>

###### Comparison of bepirovirsen treatment durations

> “A high degree of variability in both treatment arms, indicated by wide overlapping confidence intervals (CI), prevented a clear conclusion on the optimal bepirovirsen treatment duration to include in sequential therapy with Peg-IFN (Fig. S10).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.3-15"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724?tab=results)

<a id="topic-3.1.5.8.3-16"></a>

###### 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.”

Source: [Joshi et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12923464/)

<a id="topic-3.1.5.8.3-17"></a>

###### Longer-term follow-up of responders in B-Sure

> “Up to 12 months’ durability of functional cure with bepirovirsen plus Peg-IFN sequential therapy in B-Together responders: B-Sure study”
> “Data will be presented from a sub-analysis from the B-Sure phase II study, evaluating the achievement and duration of a functional cure in CHB patients who responded to treatment with bepirovirsen followed by Peg-IFN, a type of immune-boosting therapy.”

Source: [GSK press release, AASLD 2025 (2025)](https://www.gsk.com/en-gb/media/press-releases/gsk-presents-data-from-its-advancing-liver-pipeline-at-aasld-2025/)

<a id="topic-3.1.5.8.3-18"></a>

###### Follow-up of responders planned in B-Sure

> “Long-term durability of response will be evaluated in the B-Sure trial (NCT04954859),23 which will follow responders from B-Together and B-Clear for an additional 33 months and allows for cessation of NA therapy and assessment of functional cure.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="heading-3.1.5.8.4"></a>

###### 3.1.5.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.5.8.5"></a>

###### 3.1.5.8.5 Safety Results

<a id="topic-3.1.5.8.5-1"></a>

###### Overall adverse events, discontinuations, serious adverse events, and deaths

> “The proportion of participants who experienced AEs in the bepirovirsen and Peg-IFN treatment windows was similar between treatment arms (95% vs. 98%), with most AEs considered treatment related (Table 4). Few AEs led to treatment discontinuation (4%; 3 during bepirovirsen and 1 during Peg-IFN treatment).”
> “There were no reports of serious liver injury, clinically significant bleeding events, renal injury, or vascular injury linked to alternate complement pathway activation. Nine serious AEs (SAEs) were reported in eight participants, five during bepirovirsen treatment (one considered treatment related) and three in the off-treatment period. No deaths were reported. The most common AEs were injection-site erythema (Table S7).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.5-2"></a>

###### 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)” |

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.5-3"></a>

###### 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)” |

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.5-4"></a>

###### Adverse events during the Peg-IFN treatment window

| Event, n (%) | Arm 1 (n = 55) | Arm 2 (n = 53) | Total (N = 108) |
| --- | --- | --- | --- |
| Any AE | “46 (84)” | “43 (81)” | “89 (82)” |
| Any grade 3 and 4 event | “17 (31)” | “8 (15)” | “25 (23)” |
| AESI: ALT increase | “16 (29)” | “5 (9)” | “21 (19)” |
| AESI: thrombocytopenia | “21 (38)” | “16 (30)” | “37 (34)” |
| Neutropenia | “10 (18)” | “11 (21)” | “21 (19)” |

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.5-5"></a>

###### ALT increases and the serious adverse event of drug-induced liver injury

> “For AESIs associated with increased ALT, a larger proportion of participants reported events in Arm 1 compared with Arm 2 (49% vs. 21%).”
> “Increases in ALT levels observed throughout the study were asymptomatic and resolved without increases in bilirubin. One ALT increase was reported as an SAE of drug-induced liver injury. The participant was not hospitalised for the event and reported no signs or symptoms associated with the ALT increase. The treatment was held at Week 7 and withdrawn at Week 9, when the participant met the stopping criteria per protocol (ALT >10x ULN for ≥4 weeks).”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.5-6"></a>

###### Grade 3 and 4 events and DAIDS laboratory grading

> “Grade 3 and 4 events occurred in 33% of participants during the bepirovirsen period and 23% in the Peg-IFN period. Some Grade 3/4 AEs were driven by Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS) grading for laboratory changes and may not have been correlated with clinical severity.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.5-7"></a>

###### Platelet count decline

> “A decline in platelet count was observed over the course of sequential treatment that improved in the follow-up period; compared with Peg-IFN, the influence of bepirovirsen was minimal.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.8.5-8"></a>

###### 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%)” |

Source: [ClinicalTrials.gov NCT04676724](https://clinicaltrials.gov/study/NCT04676724?tab=results)

<a id="heading-3.1.5.9"></a>

##### 3.1.5.9 Study Limitations

<a id="topic-3.1.5.9-1"></a>

###### 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.

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010); [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.5.9-2"></a>

###### Absence of a bepirovirsen-only control group

> “Firstly, the B-Together study design lacks control groups, i.e. bepirovirsen 300 mg for 12 or 24 weeks alone, which limits comparisons of bepirovirsen and Peg-IFN sequential therapy with bepirovirsen alone. Thus, the study uses indirect comparisons to the B-Clear study.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.9-3"></a>

###### Effect of the COVID-19 pandemic on Arm 1

> “Secondly, the COVID-19 pandemic disproportionately affected Arm 1 during the Peg-IFN treatment period, with nine participants missing 50 Peg-IFN dosing visits on Arm 1.”
> “However, the modelled point estimate may still have underestimated the response rate had this confounding not occurred.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.9-4"></a>

###### Conservative primary outcome definition

> “Secondly, the primary outcome definition of HBsAg and HBV DNA <LLOQ maintained at all timepoints off-treatment is highly conservative and likely underestimated the proportion of participants with response.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.9-5"></a>

###### Small arms and heterogeneity limit between-arm comparison

> “However, it is difficult to fully compare the differences in arms, owing to both the relatively small study size and the heterogeneity observed in the study population. Due to the small participant numbers in each arm and a high level of variability (wide and overlapping 95% CIs), there was uncertainty regarding between-treatment differences.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.9-6"></a>

###### Hypothesized improvement not shown

> “While the study did not show the substantive improvement in bepirovirsen response we hypothesised, further studies of sequential or combination therapy with bepirovirsen and other agents such as HBsAg-lowering agents (e.g. siRNA) or different immunomodulators are being considered to improve response rates and increase the treatable population, and ultimately deliver functional cure to more patients.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="topic-3.1.5.9-7"></a>

###### Limitations of the post hoc biomarker analysis

> “These analyses were opportunistic and not powered.”
> “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.”
> “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.”

Source: [Joshi et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12923464/)

<a id="topic-3.1.5.9-8"></a>

###### Applicability: label recommendation on peginterferon alfa-2a

> “Concomitant administration of HIBSAGO and peginterferon alfa-2a is not recommended due to the potential for an exacerbated risk of increased ALT, decreased platelet count, and immune-mediated effects.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.5.9-9"></a>

###### Funding, sponsor role, and author employment

> “This trial was funded by GSK (GSK ID: 209348/NCT04676724). The sponsor, GSK, was involved in the design, conduct, and analysis of the trial and wrote the trial report.”
> “SD, MP, LF, ML, TG, JL, DL, GMG, HP, ASY, RE, SK and DT are employed by GSK and hold financial equities in GSK.”

Source: [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

<a id="heading-3.1.6"></a>

#### 3.1.6 ISIS 505358-CS3 Phase 2a Study

<a id="heading-3.1.6.1"></a>

##### 3.1.6.1 Objective

<a id="topic-3.1.6.1-1"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.1-2"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.1-3"></a>

###### 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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.1-4"></a>

###### Objective as registered

> “To examine the safety and tolerability of IONIS-HBVRx administration to treatment-naive patients with chronic hepatitis B virus infection”

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602)

<a id="heading-3.1.6.2"></a>

##### 3.1.6.2 Location and Study Date

<a id="topic-3.1.6.2-1"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.2-2"></a>

###### Number of centers stated in the abstract

> “Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml−1 were enrolled from seven centers across Hong Kong and the Republic of Korea”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.2-3"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602)

<a id="topic-3.1.6.2-4"></a>

###### Sponsorship at the time of the trial

> “Study NCT02981602, currently sponsored by GlaxoSmithKline (study ID 205695), was at the time of the trial, supported by GlaxoSmithKline and sponsored by Ionis Pharmaceuticals, Inc. (ISIS 505358-CS3).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="heading-3.1.6.3"></a>

##### 3.1.6.3 Study Design

<a id="topic-3.1.6.3-1"></a>

###### 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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.3-2"></a>

###### Randomization and blinding

> “Patients were randomized (3:1 within each dose cohort) to bepirovirsen or placebo according to the randomization schedule (permuted block).”
> “All participants, study monitors, study center personnel and contract research organization personnel were blinded to treatment assignment.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.3-3"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.3-4"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.3-5"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602)

<a id="heading-3.1.6.4"></a>

##### 3.1.6.4 Eligibility Criteria

<a id="topic-3.1.6.4-1"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.4-2"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.4-3"></a>

###### Registered age range and cirrhosis criteria

> “Age 18 to 70 years”
> “Fibroscan > 12 KPa, within 12 months of Screening, or”
> “BMI > 35 kg/m2”

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602)

<a id="heading-3.1.6.5"></a>

##### 3.1.6.5 Treatment

<a id="topic-3.1.6.5-1"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.5-2"></a>

###### 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.”
> “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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.5-3"></a>

###### Registered administration by cohort

| Cohort | Quoted description |
| --- | --- |
| Cohort 1 | “Treatment-naive participants were subcutaneously administered GSK3228836 150 mg on Days 1, 4, 8, 11, 15 and 22 by trained study center personnel in abdomen, upper arm or thigh.” |
| Cohorts 2 and 3 | “Treatment-naive participants were subcutaneously administered GSK3228836 300 mg on Days 1, 4, 8, 11, 15 and 22 by trained study center personnel in abdomen, upper arm or thigh.” |
| Cohort 4 | “Participants on stable nucleos(t)ide treatment were subcutaneously administered GSK3228836 300 mg on Days 1, 4, 8, 11, 15 and 22 by trained study center personnel in abdomen, upper arm or thigh.” |

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602?tab=results)

<a id="heading-3.1.6.6"></a>

##### 3.1.6.6 Study Outcomes

<a id="heading-3.1.6.6.1"></a>

###### 3.1.6.6.1 Rationale for Using Adverse Events and Clinical Laboratory Assessments as the Primary Endpoints

<a id="topic-3.1.6.6.1-1"></a>

###### 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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.6.1-2"></a>

###### No primary efficacy endpoint in the protocol

> “There is no primary efficacy endpoint.”

Source: [Ionis ISIS 505358-CS3 protocol (2019)](https://cdn.clinicaltrials.gov/large-docs/02/NCT02981602/Prot_002.pdf)

<a id="topic-3.1.6.6.1-3"></a>

###### 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)”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.6.1-4"></a>

###### 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”
> “Functional cure is associated with improved clinical outcomes and allows patients to be off-therapy with a minimal risk of relapse”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.6.1-5"></a>

###### Protocol background on HBsAg loss as the treatment endpoint

> “In both HBeAg positive and HBeAg negative CHB, the ultimate treatment endpoint is loss of detectable serum HBsAg (Lok and McMahon 2009; EASL 2012).”

Source: [Ionis ISIS 505358-CS3 protocol (2019)](https://cdn.clinicaltrials.gov/large-docs/02/NCT02981602/Prot_002.pdf)

<a id="topic-3.1.6.6.1-6"></a>

###### Day 29 as the time of antiviral assessment

> “The main assessments of single-agent treatment effects of bepirovirsen were performed on day 29, 7 d after the last dose of study drug (bepirovirsen or placebo).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.6.1-7"></a>

###### Dose-limiting toxicity definition

> “Dose escalation and study enrollment ceased in the event of death of one patient or the occurrence of the same dose-limiting toxicity in two patients within one dose cohort.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="heading-3.1.6.7"></a>

##### 3.1.6.7 Statistical Analysis Description

<a id="heading-3.1.6.7.1"></a>

###### 3.1.6.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.6.7.1-1"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.7.1-2"></a>

###### Planned size of the on-NA cohort

> “Approximately eight patients were planned.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.7.1-3"></a>

###### Participants enrolled and the combination of cohorts 2 and 3

> “A total of 31 participants were enrolled and received either GSK3228836 or placebo. In Cohort 3 participants were administered GSK3228836 300 milligram [mg] instead of 450 mg as per sponsor's decision, hence Cohort 2 and Cohort 3 have been combined.”

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602?tab=results)

<a id="topic-3.1.6.7.1-4"></a>

###### Participants analyzed

> “Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="heading-3.1.6.7.2"></a>

###### 3.1.6.7.2 Description of Analysis Sets

<a id="topic-3.1.6.7.2-1"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.7.2-2"></a>

###### 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.”
> “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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.7.2-3"></a>

###### Unplanned unblinded interim analyses

> “No formal interim analysis was planned. However, an unblinded interim analysis for treatment-naïve dose cohorts was performed after all treatment-naïve patients had completed their day 29 assessments.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.7.2-4"></a>

###### Protocol definition of the safety set

> “The Safety Set will include all randomized patients who received at least 1 dose of ISIS 505358 or placebo.”

Source: [Ionis ISIS 505358-CS3 protocol (2019)](https://cdn.clinicaltrials.gov/large-docs/02/NCT02981602/Prot_002.pdf)

<a id="heading-3.1.6.8"></a>

##### 3.1.6.8 Results

<a id="heading-3.1.6.8.1"></a>

###### 3.1.6.8.1 Participant Disposition

<a id="topic-3.1.6.8.1-1"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.1-2"></a>

###### Registry participant flow

| Disposition | Cohort 1, 150 mg | Cohorts 2 and 3, 300 mg | Cohorts 1 to 3, placebo | Cohort 4, 300 mg | Cohort 4, placebo |
| --- | --- | --- | --- | --- | --- |
| Started | “6” | “12” | “6” | “5” | “2” |
| Completed | “6” | “12” | “6” | “4” | “2” |
| Not completed (adverse event) | “0” | “0” | “0” | “1” | “0” |

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602?tab=results)

<a id="heading-3.1.6.8.2"></a>

###### 3.1.6.8.2 Baseline Characteristics

<a id="topic-3.1.6.8.2-1"></a>

###### Comparability of arms

> “Demographics and baseline characteristics were similar between treatment arms (Table 1).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.2-2"></a>

###### Demographics and baseline characteristics (safety population)

| Characteristic | Treatment-naive, 150 mg (n = 6) | Treatment-naive, 300 mg (n = 12) | Treatment-naive, placebo (n = 6) | On-NA, 300 mg (n = 5) | On-NA, placebo (n = 2) |
| --- | --- | --- | --- | --- | --- |
| Age, mean (s.d.), years | “42.5 (11.22)” | “42.6 (14.12)” | “49.3 (12.66)” | “48.4 (7.40)” | “37.0 (2.83)” |
| Male, n (%) | “3 (50.0)” | “4 (33.3)” | “4 (66.7)” | “4 (80.0)” | “1 (50.0)” |
| Asian, n (%) | “6 (100.0)” | “12 (100.0)” | “6 (100.0)” | “5 (100.0)” | “2 (100.0)” |
| HBsAg, mean (s.d.), log10 IU/ml | “3.57 (1.244)” | “3.89 (1.056)” | “3.21 (1.304)” | “2.78 (0.363)” | “3.77 (1.018)” |
| HBeAg positive, n (%) | “5 (83.3)” | “6 (50.0)” | “2 (33.3)” | “0 (0)” | “0 (0)” |
| HBV DNA, mean (s.d.), log10 IU/ml | “7.41 (1.396)” | “6.77 (1.892)” | “5.57 (2.121)” | “<1.30 (0.000)a” | “<1.30 (0.000)a” |
| ALT, mean (s.d.), U/l | “53.2 (35.52)” | “42.9 (31.77)” | “35.8 (13.29)” | “20.8 (9.31)” | “15.0 (7.07)” |
| HBV genotype B, n (%) | “2 (33.3)” | “4 (33.3)” | “2 (33.3)” | “0” | “0” |
| HBV genotype C, n (%) | “4 (66.7)” | “8 (66.7)” | “4 (66.7)” | “0” | “0” |
| HBV genotype indeterminate, n (%) | “0” | “0” | “0” | “5 (100.0)b” | “2 (100.0)b” |

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.2-3"></a>

###### Genotype indeterminate in the on-NA cohort

> “Historical data not available and HBV DNA levels were below the LLOQ to establish genotyping.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.2-4"></a>

###### Registry total age

> “44.5(11.90)”

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602?tab=results)

<a id="heading-3.1.6.8.3"></a>

###### 3.1.6.8.3 Efficacy Results

<a id="topic-3.1.6.8.3-1"></a>

###### 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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.3-2"></a>

###### 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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.3-3"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.3-4"></a>

###### 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.”
> “The fourth patient had no decrease in HBsAg.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.3-5"></a>

###### HBsAg loss at day 29 and week 31 in the registry results

| Time point | Cohort 1, 150 mg (%) | Cohorts 2 and 3, 300 mg (%) | Cohorts 1 to 3, placebo (%) | Cohort 4, 300 mg (%) | Cohort 4, placebo (%) |
| --- | --- | --- | --- | --- | --- |
| Participants analyzed | “6” | “12” | “6” | “5” | “2” |
| Day 29 | “0” | “16.7” | “0” | “20.0” | “0” |
| Week 31 | “0” | “0” | “0” | “0” | “0” |

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602?tab=results)

<a id="topic-3.1.6.8.3-6"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602?tab=results)

<a id="topic-3.1.6.8.3-7"></a>

###### 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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.3-8"></a>

###### Response by HBeAg status

> “All four patients who reached undetectable HBsAg levels were HBeAg negative.”
> “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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.3-9"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.3-10"></a>

###### Binding site sequencing

> “No sequence alterations were found in any of the samples assessed at baseline (n = 25), day 29 (n = 17) and day 113 (n = 7).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="heading-3.1.6.8.4"></a>

###### 3.1.6.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.6.8.5"></a>

###### 3.1.6.8.5 Safety Results

<a id="topic-3.1.6.8.5-1"></a>

###### 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%).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.5-2"></a>

###### Selected treatment-emergent adverse events (safety population)

| TEAE, n (%) | Treatment-naive, 150 mg (n = 6) | Treatment-naive, 300 mg (n = 12) | Treatment-naive, placebo (n = 6) | On-NA, 300 mg (n = 5) | On-NA, placebo (n = 2) |
| --- | --- | --- | --- | --- | --- |
| Patients with ≥1 TEAE | “5 (83.3)” | “6 (50.0)” | “3 (50.0)” | “3 (60.0)” | “1 (50.0)” |
| Injection site erythema | “0” | “3 (25.0)” | “0” | “1 (20.0)” | “0” |
| Injection site pruritus | “2 (33.3)” | “1 (8.3)” | “0” | “0” | “0” |
| Pyrexia | “1 (16.7)” | “3 (25.0)” | “1 (16.7)” | “1 (20.0)” | “0” |
| Nausea | “1 (16.7)” | “2 (16.7)” | “1 (16.7)” | “0” | “0” |
| ALT increased | “0” | “2 (16.7)” | “0” | “0” | “0” |
| Headache | “0” | “2 (16.7)” | “1 (16.7)” | “0” | “1 (50.0)” |

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.5-3"></a>

###### 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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.5-4"></a>

###### 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.”
> “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.”
> “There were no concurrent changes in bilirubin (total and direct) for any patient.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.5-5"></a>

###### 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).”
> “ALT and AST levels decreased substantially within 2 weeks and returned to baseline by week 17. The patient was asymptomatic throughout.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.5-6"></a>

###### 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.”
> “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.”
> “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).”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.8.5-7"></a>

###### 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%)” |

Source: [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602?tab=results)

<a id="heading-3.1.6.9"></a>

##### 3.1.6.9 Study Limitations

<a id="topic-3.1.6.9-1"></a>

###### 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.

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/); [ClinicalTrials.gov NCT02981602](https://clinicaltrials.gov/study/NCT02981602?tab=results); [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.6.9-2"></a>

###### 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.”
> “Furthermore, the study did not provide insight into effects in the liver due to the absence of liver biopsies.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.9-3"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.9-4"></a>

###### 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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.9-5"></a>

###### No adjustment for multiple comparisons

> “All comparisons were prespecified with no adjustment for multiple comparisons.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.9-6"></a>

###### Variable durability of response

> “Among the most robust responders, the HBsAg response was rapid and was prolonged after the end of treatment; however, the durability of response was variable.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="topic-3.1.6.9-7"></a>

###### 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.”
> “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.”

Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/)

<a id="heading-3.1.7"></a>

#### 3.1.7 B-Fine

<a id="heading-3.1.7.1"></a>

##### 3.1.7.1 Objective

<a id="topic-3.1.7.1-1"></a>

###### Primary objective

> “Efficacy: To assess the effect of 12 weeks of GSK3228836 on serum hepatitis B virus surface antigen (HBsAg) levels in participants with CHB”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.1-2"></a>

###### Mechanistic rationale

> “B-Fine is an exploratory study of the therapeutic mechanism of GSK3228836 in participants with chronic hepatitis B (CHB) on stable nucleos(t)ide therapy.”
> “Repeat fine needle aspirates of the liver will be performed to enable analysis of liver-resident immune cells to investigate any immunomodulatory properties of GSK3228836 and to study the biology of underlying treatment-associated liver flares.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.1-3"></a>

###### Study hypothesis

> “Study Hypothesis: GSK3228836 treatment will result in phenotypic changes in intrahepatic immunity associated with loss of HBsAg and treatment-emergent changes in ALT”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.1-4"></a>

###### Questions the mechanistic investigation addresses

> “To determine whether GSK3228836 has an immunomodulatory mechanism of action in addition to its previously described direct antiviral effects on HBV mRNA.”
> “To investigate the relationship between GSK3228836-mediated suppression of HBsAg, ALT flares and the potential for functional cure.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.1-5"></a>

###### Objective as registered

> “It will investigate the virologic and immunologic correlates of hepatitis B virus surface antigen (HBsAg) loss observed in participants when treated for 12 weeks with 300 milligrams (mg) GSK3228836.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="heading-3.1.7.2"></a>

##### 3.1.7.2 Location and Study Date

<a id="topic-3.1.7.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="topic-3.1.7.2-2"></a>

###### Countries of the listed sites

> “Boston, Massachusetts, United States, 02114”
> “Toronto, Ontario, Canada, M5G 2C4”
> “Rotterdam, Netherlands, 3015 GD”
> “London, United Kingdom, E1 1BB”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="topic-3.1.7.2-3"></a>

###### Regulatory identifiers and protocol approval date

> “EudraCT: 2020-002000-39”
> “Approval Date: 15-MAR-2021”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="heading-3.1.7.3"></a>

##### 3.1.7.3 Study Design

<a id="topic-3.1.7.3-1"></a>

###### Phase IIa, multicentre, open-label, single-arm design with repeat liver fine needle aspiration

> “This study is a Phase IIa, multi-centre open label exploratory study of the therapeutic mechanism of GSK3228836 in participants with HBeAg-negative CHB on stable nucleos(t)ide therapy using repeat fine needle aspirations of the liver for intrahepatic immunophenotyping (see Section 1.2).”
> “After the 12 weeks of dosing with GSK3228836, there will be a post-treatment follow-up period of 24 weeks. An Independent Data Monitoring Committee (IDMC) will review the data (see Section 10.1.5).”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.3-2"></a>

###### Number and timing of fine needle aspirates

> “In study 212602, it is proposed to perform a total of 5 FNAs at preselected timepoints (plus up to 1 optional FNA) during the 45-week study duration (see Section 1.2).”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.3-3"></a>

###### Study duration and visit frequency

> “Study Duration: 37 weeks (45 weeks if include screening and flexible visit windows)”
> “Visit Frequency: Twice a week for the first 2 weeks, once a week through Week 14, once at Week 16, and once every 4 weeks thereafter”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.3-4"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="heading-3.1.7.4"></a>

##### 3.1.7.4 Eligibility Criteria

<a id="topic-3.1.7.4-1"></a>

###### Key registered inclusion criteria

> “Participants should be at least 18 years of age at the time of signing the informed consent.”
> “Participants who have documented chronic HBV infection >=6 months prior to screening and currently receiving stable nucleos(t)ide analogue therapy, defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.”
> “Plasma or serum HBsAg concentration >100 IU/mL”
> “Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.”
> “HBeAg-negative”
> “ALT less than or equal to (<=)2 times ULN”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="topic-3.1.7.4-2"></a>

###### Key registered exclusion criteria

> “Liver biopsy showing Metavir 4 or equivalent”
> “Liver stiffness >12 kilopascals (kPa)”
> “Currently taking, or took within 12 months of screening, any interferon-containing therapy.”
> “Platelet count <140 times 10^9/liter (L)”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="topic-3.1.7.4-3"></a>

###### Rationale for enrolling HBeAg-negative participants on NA therapy

> “In study 212602 (B-Fine), participants expected to have the highest chance of achieving HBsAg level <LLOQ with 12 weeks of treatment with GSK3228836 will be enrolled.”
> “As HBeAg-negative patients typically have lower levels of serum HBsAg than HBeAg-positive patients, the HBeAg-negative population has been selected for study 212602 in order to enrich for potential responders.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="heading-3.1.7.5"></a>

##### 3.1.7.5 Treatment

<a id="topic-3.1.7.5-1"></a>

###### Bepirovirsen dose, loading doses, and duration

> “Participants on stable nucleos(t)ide therapy will receive GSK3228836 300 mg subcutaneously (SC) weekly once for 12 weeks along with a loading dose of GSK3228836 300 mg in Week 1 (Day 4) and Week 2 (Day 11).”
> “GSK3228836 will be available as a clear colorless to slightly yellow solution for injection in 150 mg/milliliters (mL) vial to be administered SC once weekly.”
> “Participants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleos(t)ide therapy for the duration of the study.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="topic-3.1.7.5-2"></a>

###### Rationale for 12 weeks of treatment

> “Twelve weeks duration of treatment with 300 mg GSK3228836 has been selected as optimal to assess the primary endpoint of achieving HBsAg < LLOQ in study 212602.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.5-3"></a>

###### Dose adjustments

> “There are no plans for dose adjustments.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="heading-3.1.7.6"></a>

##### 3.1.7.6 Study Outcomes

<a id="heading-3.1.7.6.1"></a>

###### 3.1.7.6.1 Rationale for Using HBsAg Below the Lower Limit of Quantitation by Week 12 as the Primary Endpoint

<a id="topic-3.1.7.6.1-1"></a>

###### Primary endpoint and estimation approach

> “The primary endpoint is achieving serum HBsAg level <LLOQ by Week 12 (at any time point up to and including Week 12) without the use of PEG-interferon or other immunomodulator therapies in CHB participants who receive at least one dose of IP.”
> “An estimation approach with no hypothesis testing will be used to address the primary objective.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.6.1-2"></a>

###### HBsAg loss as the treatment endpoint in chronic hepatitis B

> “In both HBeAg-positive and HBeAg-negative CHB, the ultimate treatment endpoint is loss of detectable serum hepatitis B surface antigen (HBsAg) and serum HBV DNA [Lok, 2009; EASL, 2012].”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.6.1-3"></a>

###### Rationale from the phase 2a study for a longer treatment duration

> “Taken together, the data suggest that a longer duration of treatment with GSK3228836 may be required to increase the rate of participants achieving HBsAg levels <LLOQ.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.6.1-4"></a>

###### Registered primary outcome measure

> “Percentage of participants achieving serum HBsAg level <LLOQ were reported. Percentage values are rounded-off.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="topic-3.1.7.6.1-5"></a>

###### Secondary endpoints: sustained HBsAg response and sustained virologic response

> “Sustained HBsAg response is defined as HBsAg <LLOQ for 24 weeks from end of GSK3228836 treatment. Percentage values are rounded-off.”
> “Sustained virologic response is defined as HBsAg <LLOQ and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) <LLOQ for 24 weeks from end of GSK3228836 treatment. Percentage values are rounded-off.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="topic-3.1.7.6.1-6"></a>

###### Secondary ALT endpoint: time to maximum ALT

> “Time to maximum ALT (maximum peak in ALT) during 36 week (treatment + follow-up) is defined as time from Baseline to the time of first peak in ALT.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956)

<a id="heading-3.1.7.7"></a>

##### 3.1.7.7 Statistical Analysis Description

<a id="heading-3.1.7.7.1"></a>

###### 3.1.7.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.7.7.1-1"></a>

###### Planned enrollment

> “Number of Participants: The study will enrol approximately 20 participants, but no more than 24.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.7.1-2"></a>

###### Bayesian operating characteristics for 20 participants

> “With a sample size of 20 participants, if there are at least 12 participants achieving HBsAg <LLOQ (observed percent of 60%) then the posterior probability that the true percent is greater than 50% will be greater than 75%.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.7.1-3"></a>

###### Conditions for increasing the sample size

> “In certain cases, including but not limited to higher than anticipated drop-out rate, higher than anticipated rates of efficacy, or large variability in ALT flare patterns, the sample size may be increased to no more than 24.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.7.1-4"></a>

###### Participants enrolled and analyzed

> “A total of 12 participants were enrolled in this study.”
> “Intent to Treat (ITT) Set that included all participants who received at least one dose of study treatment.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results)

<a id="heading-3.1.7.7.2"></a>

###### 3.1.7.7.2 Description of Analysis Sets

<a id="topic-3.1.7.7.2-1"></a>

###### 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.” |

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.7.2-2"></a>

###### Handling of intercurrent events and immunomodulator use

> “Intercurrent events: Discontinuation of, interruption of, and adherence to IP will be ignored (treatment policy).”
> “If PEG-interferon or other immunomodulator therapies are used, then the participant’s primary outcome will be treated as a failure.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.7.2-3"></a>

###### Primary analysis: point estimate with 95% credible interval

> “Point estimate of the percentage as well as the 95% credible interval (Highest Density Interval, HDI) of participants achieving serum HBsAg level <LLOQ by Week 12 will be provided.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="topic-3.1.7.7.2-4"></a>

###### Safety population in the registry results

> “All-cause mortality, Serious adverse events and non-serious adverse events were reported for the Safety Population which consisted of all participants who received at least one dose of study treatment.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results)

<a id="heading-3.1.7.8"></a>

##### 3.1.7.8 Results

<a id="heading-3.1.7.8.1"></a>

###### 3.1.7.8.1 Participant Disposition

<a id="topic-3.1.7.8.1-1"></a>

###### Registry participant flow

| Disposition | Bepirovirsen 300 mg |
| --- | --- |
| Started | “12” |
| Completed | “11” |
| Not completed | “1” |
| Reason not completed | “Withdrawal by Subject” |

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results)

<a id="heading-3.1.7.8.2"></a>

###### 3.1.7.8.2 Baseline Characteristics

<a id="topic-3.1.7.8.2-1"></a>

###### Age

> “48.8(8.48)”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results)

<a id="topic-3.1.7.8.2-2"></a>

###### Sex and race reported only as a de-identified category

> “Gender categories (with 0<n<11) are combined into one 'De-identified' category to maintain participant confidentiality and privacy, as they could lead to participant re-identification.”
> “Race categories (with 0<n<11) are combined into one 'De-identified' category to maintain participant confidentiality and privacy, as they could lead to participant re-identification.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results)

<a id="heading-3.1.7.8.3"></a>

###### 3.1.7.8.3 Efficacy Results

<a id="topic-3.1.7.8.3-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results)

<a id="topic-3.1.7.8.3-2"></a>

###### Time to maximum ALT

> “(27.1 to NA)”
> “NA indicates median and 95% CI (upper limit) could not be derived, as <50% of participants experienced the event within the treatment arm.”

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results)

<a id="topic-3.1.7.8.3-3"></a>

###### Intrahepatic and peripheral immunophenotyping presented at AASLD 2025

> “Intrahepatic immunophenotyping of participants with chronic hepatitis B receiving bepirovirsen in the B-Fine study reveals diverse changes in immunological status”
> “Intrahepatic and peripheral immunophenotyping of participants with chronic hepatitis B receiving bepirovirsen in the B-Fine study strongly suggests that bepirovirsen may trigger a humoral response”

Source: [GSK press release, AASLD 2025 (2025)](https://www.gsk.com/en-gb/media/press-releases/gsk-presents-data-from-its-advancing-liver-pipeline-at-aasld-2025/)

<a id="heading-3.1.7.8.4"></a>

###### 3.1.7.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.7.8.5"></a>

###### 3.1.7.8.5 Safety Results

<a id="topic-3.1.7.8.5-1"></a>

###### 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%)” |

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results)

<a id="heading-3.1.7.9"></a>

##### 3.1.7.9 Study Limitations

<a id="topic-3.1.7.9-1"></a>

###### 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.

Source: [ClinicalTrials.gov NCT04544956](https://clinicaltrials.gov/study/NCT04544956?tab=results); [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf); [GSK press release, AASLD 2025 (2025)](https://www.gsk.com/en-gb/media/press-releases/gsk-presents-data-from-its-advancing-liver-pipeline-at-aasld-2025/); [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.7.9-2"></a>

###### Exploratory design without hypothesis testing

> “An estimation approach with no hypothesis testing will be used to address the primary objective.”

Source: [GSK 212602 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/56/NCT04544956/Prot_000.pdf)

<a id="heading-3.1.8"></a>

#### 3.1.8 B-United

<a id="heading-3.1.8.1"></a>

##### 3.1.8.1 Objective

<a id="topic-3.1.8.1-1"></a>

###### Aim stated in the registry record

> “The study is intended to evaluate the efficacy and safety of 2 different doses of DAP/TOM followed by bepirovirsen in participants living with CHB on standard of care nucleos(t)ide analogue (NA) therapy. The study also aims to identify an optimal dose of DAP/TOM for sequenced therapy with bepirovirsen for further clinical development and to assess the contribution of DAP/TOM to the sequential regimen. The study will also include an optional long-term follow-up (LTFU) extension stage for eligible participants.”

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.1-2"></a>

###### Purpose of the sequential regimen stated by the sponsor

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

Source: [GSK Q1 2026 results (2026)](https://www.gsk.com/media/hpgfxwxv/q1-2026-results-announcement.pdf)

<a id="heading-3.1.8.2"></a>

##### 3.1.8.2 Location and Study Date

<a id="topic-3.1.8.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.2-2"></a>

###### Number of study locations

> “This study has 80 locations”

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.2-3"></a>

###### Trial start and status reported by the sponsor

> “Phase IIb trials for this sequential therapy started in Q4 2024.”

Source: [GSK Q1 2026 results (2026)](https://www.gsk.com/media/hpgfxwxv/q1-2026-results-announcement.pdf)

<a id="heading-3.1.8.3"></a>

##### 3.1.8.3 Study Design

<a id="topic-3.1.8.3-1"></a>

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

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

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.3-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.3-3"></a>

###### Treatment stages and nucleos(t)ide analogue discontinuation

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

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="heading-3.1.8.4"></a>

##### 3.1.8.4 Eligibility Criteria

<a id="topic-3.1.8.4-1"></a>

###### Key inclusion criteria

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

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.4-2"></a>

###### Key exclusion criteria

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

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="heading-3.1.8.5"></a>

##### 3.1.8.5 Treatment

<a id="topic-3.1.8.5-1"></a>

###### Treatment arms by baseline HBsAg level and DAP/TOM dose

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

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.5-2"></a>

###### Bepirovirsen in treatment stage 2

> “After Placebo treatment, eligible participants will receive bepirovirsen in Treatment Stage 2.”
> “Bepirovirsen will be administered”

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="heading-3.1.8.6"></a>

##### 3.1.8.6 Study Outcomes

<a id="heading-3.1.8.6.1"></a>

###### 3.1.8.6.1 Rationale for Using Functional Cure (HBsAg Not Detected and HBV DNA Below the LLOQ Off Treatment) as the Primary Endpoint

<a id="topic-3.1.8.6.1-1"></a>

###### Registered primary outcome: functional cure off all HBV treatment

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

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.6.1-2"></a>

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

> “Number of participants achieving functional cure with high Baseline HBsAg level”
> “Number of participants achieving functional cure with low Baseline HBsAg level compared against placebo + bepirovirsen arm”
> “The number of participants with undetected HBsAg and HBV DNA <LLOQ at the end of bepirovirsen treatment will be reported.”

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="topic-3.1.8.6.1-3"></a>

###### 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.”
> “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.”

Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/)

<a id="topic-3.1.8.6.1-4"></a>

###### Response to bepirovirsen alone by baseline HBsAg level

> “Response rates declined with increasing baseline HBsAg levels and fell below 10% for genotypes B and C at baseline HBsAg levels exceeding 1,000 IU/mL.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.8.7"></a>

##### 3.1.8.7 Statistical Analysis Description

<a id="heading-3.1.8.7.1"></a>

###### 3.1.8.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.8.7.1-1"></a>

###### Enrollment in the registry record

| Field | Registry entry |
| --- | --- |
| Enrollment (actual) | “283” |

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414)

<a id="heading-3.1.8.7.2"></a>

###### 3.1.8.7.2 Description of Analysis Sets

No evidence found.

<a id="heading-3.1.8.8"></a>

##### 3.1.8.8 Results

<a id="heading-3.1.8.8.1"></a>

###### 3.1.8.8.1 Participant Disposition

No evidence found.

<a id="heading-3.1.8.8.2"></a>

###### 3.1.8.8.2 Baseline Characteristics

No evidence found.

<a id="heading-3.1.8.8.3"></a>

###### 3.1.8.8.3 Efficacy Results

No evidence found.

<a id="heading-3.1.8.8.4"></a>

###### 3.1.8.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.8.8.5"></a>

###### 3.1.8.8.5 Safety Results

No evidence found.

<a id="heading-3.1.8.9"></a>

##### 3.1.8.9 Study Limitations

<a id="topic-3.1.8.9-1"></a>

###### 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.

Source: [ClinicalTrials.gov NCT06537414](https://clinicaltrials.gov/study/NCT06537414); [GSK Q1 2026 results (2026)](https://www.gsk.com/media/hpgfxwxv/q1-2026-results-announcement.pdf)

<a id="heading-3.1.9"></a>

#### 3.1.9 B-Focus

<a id="heading-3.1.9.1"></a>

##### 3.1.9.1 Objective

<a id="topic-3.1.9.1-1"></a>

###### Aim stated in the registry record

> “This study will evaluate the efficacy and safety of bepirovirsen compared to placebo in participants with human immunodeficiency virus (HIV)/hepatitis B virus (HBV) co-infection.”

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="topic-3.1.9.1-2"></a>

###### Population excluded from the pivotal trials

> “Participants were excluded from the trial if they had a history, suspicion, or evidence of cirrhosis; co-infection with HCV, HIV, or HDV”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.9.2"></a>

##### 3.1.9.2 Location and Study Date

<a id="topic-3.1.9.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="topic-3.1.9.2-2"></a>

###### Number of study locations

> “This study has 51 locations”

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="heading-3.1.9.3"></a>

##### 3.1.9.3 Study Design

<a id="topic-3.1.9.3-1"></a>

###### Multicenter, randomized, double-blind, placebo-controlled design

> “A Multicenter, Randomized, Double-Blind, Placebo-controlled Study to Assess the Efficacy and Safety of Treatment With Bepirovirsen in Participants Living With Human Immunodeficiency Virus and Chronic Hepatitis B Virus Infection on Antiretroviral Treatment”

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="topic-3.1.9.3-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="heading-3.1.9.4"></a>

##### 3.1.9.4 Eligibility Criteria

<a id="topic-3.1.9.4-1"></a>

###### Key inclusion criteria

> “Documented chronic hepatitis B virus (HBV) infection and documented human immunodeficiency virus (HIV)-1 infection greater than equal to (>=) 12 months prior to Screening.”
> “Must be on uninterrupted antiretroviral therapy (ART) containing at least tenofovir disoproxil (TDF) or tenofovir alafenamide (TAF) plus lamivudine (3TC) or emtricitabine (FTC) for greater than (>)12 months, with no planned changes to the stable regimen over the duration of the study.”
> “Plasma or serum HBsAg concentration >100 IU/mL and <=3000 IU/mL.”
> “Plasma HIV-1 RNA concentration must be undetectable, defined as plasma HIV 1 RNA <50 copies/mL.”
> “Cluster of differentiation 4 (CD4) count >=350 cells per cubic millimeter (cells/mm^3).”
> “Alanine aminotransferase (ALT) <=2 times upper limit of normal (ULN).”

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="topic-3.1.9.4-2"></a>

###### Key exclusion criteria

> “History of or suspected liver cirrhosis and/or evidence of cirrhosis.”
> “Hepatitis D virus (HDV) defined as positive or equivocal HDV antibody regardless of HDV RNA level.”
> “Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.”
> “Prior treatment with bepirovirsen.”

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="heading-3.1.9.5"></a>

##### 3.1.9.5 Treatment

<a id="topic-3.1.9.5-1"></a>

###### Bepirovirsen or placebo arms

> “Participants will receive bepirovirsen.”
> “Participants will receive placebo.”

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="topic-3.1.9.5-2"></a>

###### Antiretroviral therapy continued in coinfected patients

> “Patients who are taking nucleos(t)ide analog reverse transcriptase inhibitors as part of antiretroviral therapy for HIV-1 and HBV coinfection must not stop taking their nucleos(t)ide analog reverse transcriptase inhibitor therapy unless an HIV healthcare provider has directed them to do so.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.9.6"></a>

##### 3.1.9.6 Study Outcomes

<a id="heading-3.1.9.6.1"></a>

###### 3.1.9.6.1 Rationale for Using HBV Virologic Response 36 Weeks After the End of Treatment as the Primary Endpoint

<a id="topic-3.1.9.6.1-1"></a>

###### Registered primary outcome: HBsAg not detected and HBV DNA below the LLOQ at week 60

> “Percentage of participants achieving hepatitis B virus (HBV) virologic response at 36 weeks after scheduled end of study treatment in absence of rescue medication”
> “HBV virologic response defined as HBV surface antigen (HBsAg) not detected and HBV deoxyribonucleic acid (DNA) less than (<) lower limit of quantification (LLOQ).”

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="topic-3.1.9.6.1-2"></a>

###### Registered secondary outcome: response at the end of treatment

> “Percentage of participants achieving HBV virologic response at the scheduled end of study treatment in absence of rescue medication”

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="topic-3.1.9.6.1-3"></a>

###### 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.”

Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/)

<a id="heading-3.1.9.7"></a>

##### 3.1.9.7 Statistical Analysis Description

<a id="heading-3.1.9.7.1"></a>

###### 3.1.9.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.9.7.1-1"></a>

###### Enrollment in the registry record

| Field | Registry entry |
| --- | --- |
| Enrollment (actual) | “153” |

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504)

<a id="heading-3.1.9.7.2"></a>

###### 3.1.9.7.2 Description of Analysis Sets

No evidence found.

<a id="heading-3.1.9.8"></a>

##### 3.1.9.8 Results

<a id="heading-3.1.9.8.1"></a>

###### 3.1.9.8.1 Participant Disposition

No evidence found.

<a id="heading-3.1.9.8.2"></a>

###### 3.1.9.8.2 Baseline Characteristics

No evidence found.

<a id="heading-3.1.9.8.3"></a>

###### 3.1.9.8.3 Efficacy Results

No evidence found.

<a id="heading-3.1.9.8.4"></a>

###### 3.1.9.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.9.8.5"></a>

###### 3.1.9.8.5 Safety Results

No evidence found.

<a id="heading-3.1.9.9"></a>

##### 3.1.9.9 Study Limitations

<a id="topic-3.1.9.9-1"></a>

###### 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.

Source: [ClinicalTrials.gov NCT06497504](https://clinicaltrials.gov/study/NCT06497504); [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.10"></a>

#### 3.1.10 Study 217023 Bepirovirsen Followed by Targeted Immunotherapy

<a id="heading-3.1.10.1"></a>

##### 3.1.10.1 Objective

<a id="topic-3.1.10.1-1"></a>

###### Aim stated in the registry record

> “This study will assess the safety, efficacy and immune response following the sequential treatment of GlaxoSmithKline's (GSK) ASO compound (GSK3228836) and CHB-TI (GSK3528869A) in participants 18 to 65 years stable on NA treatment for CHB. The aim is to quantify the efficacy of sequential therapy as well as to determine an added value of sequential therapy over GSK3228836 therapy in CHB patients treated with NAs. In addition, the study will assess the effect of different treatment durations of GSK3228836 (12 or 24 weeks) prior to initiating GSK3528869A treatment.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.1-2"></a>

###### Basis for combining HBsAg reduction with therapeutic immunization

> “Therapeutic vaccines likely require combination therapy for success.”
> “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.”

Source: [Jeng et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13496306/)

<a id="heading-3.1.10.2"></a>

##### 3.1.10.2 Location and Study Date

<a id="topic-3.1.10.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.2-2"></a>

###### Number of study locations

> “This study has 51 locations”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="heading-3.1.10.3"></a>

##### 3.1.10.3 Study Design

<a id="topic-3.1.10.3-1"></a>

###### Phase 2, single-blinded, randomized, controlled design

> “A Phase 2, Single-blinded, Randomised, Controlled Multi-country Study to Evaluate the Safety, Reactogenicity, Efficacy and Immune Response Following Sequential Treatment With an Anti-sense Oligonucleotide (ASO) Against Chronic Hepatitis B (CHB) Followed by Chronic Hepatitis B Targeted Immunotherapy (CHB-TI) in CHB Patients Receiving Nucleos(t)Ide Analogue (NA) Therapy”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.3-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.3-3"></a>

###### Follow-up period shortened during the study

> “The study follow-up period was reduced from 2 years post last dose to at least 1 year post last dose, with Visit Treatment 2-Day 505 defined as the last visit of the study.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="heading-3.1.10.4"></a>

##### 3.1.10.4 Eligibility Criteria

<a id="topic-3.1.10.4-1"></a>

###### Key inclusion criteria

> “Participants who have documented chronic HBV infection >=6 months prior to screening and currently stable on NA therapy defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.”
> “Participants with ALT <=2x upper limit of normal (ULN) (i.e., no ALT >2x ULN) documented in approximately the last 6 months.”
> “Participants with plasma or serum HBsAg concentration >100 IU/mL.”
> “Participants must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.4-2"></a>

###### Key exclusion criteria: cirrhosis definitions and laboratory thresholds

> “both AST-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7”
> “Liver biopsy (METAVIR Score F4) or Liver stiffness >12 kPa”
> “FibroScan TE score >9.6 kPa and FibroTest score >0.59 at Screening.”
> “GFR <60 mL/min/1.73m^2”
> “PLT count <140x10^9/L”
> “Positive (or borderline positive) ANCA at screening.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="heading-3.1.10.5"></a>

##### 3.1.10.5 Treatment

<a id="topic-3.1.10.5-1"></a>

###### Bepirovirsen (GSK3228836) dosing in treatment 1

> “2 doses of GSK3228836 study intervention administered subcutaneously once per week for 12 weeks (Day 1 up to Day 78) to participants in ASO12-TI and ASO12 groups, or for 24 weeks (Day 1 up to Day 162) to participants in ASO24-TI and ASO24 groups, plus loading doses administered at Day 4 and Day 11 (2 doses each day) to participants in all groups during Treatment 1 period.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.5-2"></a>

###### Targeted immunotherapy (GSK3528869A) or control in treatment 2

> “1 dose of the Chimpanzee adenovectored HBV vaccine (ChAd155-hIi-HBV) at Day 1 of Treatment 2 period.”
> “1 dose of the Modified Vaccinia Virus Ankara HBV vaccine (MVA-HBV) at Day 57 of Treatment 2 period.”
> “2 subsequent doses of the AS01B-4-adjuvanted HBc-HBs proteins (HBc-HBs/AS01B-4) administered at Day 113 and Day 169 of Treatment 2 period.”
> “4 doses of non-active control administered intramuscularly in the deltoid region of the non-dominant arm at Days 1, 57, 113 and 169 to participants in ASO24 and ASO12 control groups during Treatment 2 period.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.5-3"></a>

###### Four treatment groups

| Group | Registry entry |
| --- | --- |
| ASO24-TI | “Eligible participants receive GSK3228836 (Treatment 1) study intervention for 24 weeks of Treatment 1 period, followed by GSK3528869A (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period.” |
| ASO24 | “Eligible participants receive GSK3228836 (Treatment 1) study intervention for 24 weeks of Treatment 1 period, followed by non-active control (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period.” |
| ASO12-TI | “Eligible participants receive GSK3228836 (Treatment 1) study intervention for 12 weeks of Treatment 1 period, followed by GSK3528869A (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period.” |
| ASO12 | “Eligible participants receive GSK3228836 (Treatment 1) study intervention for 12 weeks of Treatment 1 period, followed by non-active control (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period.” |

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="heading-3.1.10.6"></a>

##### 3.1.10.6 Study Outcomes

<a id="heading-3.1.10.6.1"></a>

###### 3.1.10.6.1 Rationale for Using Grade 3 Adverse Events, Serious Adverse Events, and Sustained Virologic Response as the Primary Endpoints

<a id="topic-3.1.10.6.1-1"></a>

###### Registered primary safety outcomes

> “Percentage of participants reporting any grade 3 adverse event (AE) from first dose of GSK3228836 up to study end”
> “Percentage of participants reporting any serious adverse event (SAE) from first dose of GSK3228836 up to study end”
> “Percentage of participants reporting any adverse events of special interest (AESIs) grade 3 or higher from first dose of GSK3228836 up to study end”
> “AESI related to GSK3228836 treatment include thrombocytopenia, alanine transaminase (ALT) increases, vascular inflammation and complement activation, renal injury or injection site reactions.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.6.1-2"></a>

###### Registered primary efficacy outcome: sustained virologic response

> “Percentage of participants who achieve sustained virologic response (SVR) for 24 weeks after the planned end of active treatment in the absence of rescue medication, and difference between treatment arms (corresponding to GSK3228836 regimens)”
> “SVR is defined as Hepatitis B surface antigen (HBsAg) below (<) lower limit of quantification (LLOQ) and HBV deoxyribose nucleic acid (DNA) < LLOQ.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="topic-3.1.10.6.1-3"></a>

###### 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).”

Source: [Jeng et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13496306/)

<a id="heading-3.1.10.7"></a>

##### 3.1.10.7 Statistical Analysis Description

<a id="heading-3.1.10.7.1"></a>

###### 3.1.10.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.10.7.1-1"></a>

###### Enrollment in the registry record

| Field | Registry entry |
| --- | --- |
| Enrollment (actual) | “174” |

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297)

<a id="heading-3.1.10.7.2"></a>

###### 3.1.10.7.2 Description of Analysis Sets

No evidence found.

<a id="heading-3.1.10.8"></a>

##### 3.1.10.8 Results

<a id="heading-3.1.10.8.1"></a>

###### 3.1.10.8.1 Participant Disposition

No evidence found.

<a id="heading-3.1.10.8.2"></a>

###### 3.1.10.8.2 Baseline Characteristics

No evidence found.

<a id="heading-3.1.10.8.3"></a>

###### 3.1.10.8.3 Efficacy Results

No evidence found.

<a id="heading-3.1.10.8.4"></a>

###### 3.1.10.8.4 Health-related Quality of Life and Patient-reported Outcomes

No evidence found.

<a id="heading-3.1.10.8.5"></a>

###### 3.1.10.8.5 Safety Results

No evidence found.

<a id="heading-3.1.10.9"></a>

##### 3.1.10.9 Study Limitations

<a id="topic-3.1.10.9-1"></a>

###### 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.

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297); [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297?tab=results); [Jeng et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13496306/)

<a id="topic-3.1.10.9-2"></a>

###### Results submitted but not posted

> “No Study Results Posted on ClinicalTrials.gov”
> “The sponsor or the investigator has submitted results.”

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297?tab=results)

| Field | Registry entry |
| --- | --- |
| Results submitted to ClinicalTrials.gov | “2026-08-04” |

Source: [ClinicalTrials.gov NCT05276297](https://clinicaltrials.gov/study/NCT05276297?tab=results)

<a id="heading-3.1.11"></a>

#### 3.1.11 ISIS 505358-CS1 First-in-human Phase 1 Study

<a id="heading-3.1.11.1"></a>

##### 3.1.11.1 Objective

<a id="topic-3.1.11.1-1"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.2"></a>

##### 3.1.11.2 Location and Study Date

<a id="topic-3.1.11.2-1"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.2-2"></a>

###### 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.”
> “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).”

Source: [Clinical Pharmacology in Drug Development (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13169179/)

<a id="heading-3.1.11.3"></a>

##### 3.1.11.3 Study Design

<a id="topic-3.1.11.3-1"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.3-2"></a>

###### 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.”
> “Stopping criteria were based on changes in liver chemistry, renal function, or platelet count (Supplemental Methods).”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.4"></a>

##### 3.1.11.4 Eligibility Criteria

<a id="topic-3.1.11.4-1"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.5"></a>

##### 3.1.11.5 Treatment

<a id="topic-3.1.11.5-1"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.5-2"></a>

###### Cumulative doses in the multiple-dose cohorts

> “each participant in the multiple‐dose cohorts M1, M2, and M3 received cumulative doses of 900, 1800, or 2700 mg of bepirovirsen, respectively, over a span of 22–25 days.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.6"></a>

##### 3.1.11.6 Study Outcomes

<a id="heading-3.1.11.6.1"></a>

###### 3.1.11.6.1 Rationale for Using Safety and Tolerability as the Primary Endpoint

<a id="topic-3.1.11.6.1-1"></a>

###### Primary and secondary end points

> “The primary end point of the study was assessment of safety and tolerability of single and multiple doses of bepirovirsen. The secondary end point was assessment of plasma PK.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.6.1-2"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.7"></a>

##### 3.1.11.7 Statistical Analysis Description

<a id="heading-3.1.11.7.1"></a>

###### 3.1.11.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.11.7.1-1"></a>

###### Participants screened and randomized

> “Overall, 96 healthy volunteers were screened, among whom 28 were randomly assigned into the study (single‐dose cohorts, n = 16; multiple‐dose cohorts, n = 12) (Figure S10).”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.7.1-2"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.7.2"></a>

###### 3.1.11.7.2 Description of Analysis Sets

<a id="topic-3.1.11.7.2-1"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.7.2-2"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.8"></a>

##### 3.1.11.8 Results

<a id="heading-3.1.11.8.1"></a>

###### 3.1.11.8.1 Participant Disposition

<a id="topic-3.1.11.8.1-1"></a>

###### All randomized participants completed dosing and follow-up

> “All randomly assigned participants received all scheduled doses and completed the posttreatment follow‐up according to the study schedule.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.8.2"></a>

###### 3.1.11.8.2 Baseline Characteristics

<a id="topic-3.1.11.8.2-1"></a>

###### 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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.8.3"></a>

###### 3.1.11.8.3 Efficacy Results

<a id="topic-3.1.11.8.3-1"></a>

###### Plasma PK parameters by cohort (arithmetic mean, SD; tmax median, range; n = 3 per cohort)

| Cohort (dose) | Day | Cmax (µg/mL) | tmax (h) | AUC0–24h (µg • h/mL) | CL/F (L/h) | t1/2 (days) |
| --- | --- | --- | --- | --- | --- | --- |
| B (150 mg single dose) | 1 | “4.67 (1.69)” | “8 (6–8)” | “58.3 (25.3)” | “2.58 (0.85)” | Not reported |
| C (300 mg single dose) | 1 | “9.47 (0.34)” | “8 (6–8)” | “112 (5.71)” | “2.50 (0.13)” | Not reported |
| D (450 mg single dose) | 1 | “15.8 (4.01)” | “3 (3–8)” | “194 (21.4)” | “2.15 (0.22)” | Not reported |
| M2 (300 mg, 6 doses) | 22 | “7.93 (2.23)” | “6 (4–8)” | “103 (19.4)” | “2.03 (0.21)” | “24.2 (6.06)” |
| M3 (450 mg, 6 doses) | 22 | “11.0 (4.06)” | “3 (2–4)” | “121 (33.3)” | “2.75 (0.86)” | “24.0 (2.35)” |

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.8.3-2"></a>

###### 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).”
> “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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.8.3-3"></a>

###### Urinary excretion of full-length bepirovirsen

> “Within the first 24 hours after dosing, urinary excretion of intact full‐length bepirovirsen accounted for <2% of the administered dose across all dose levels evaluated.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.8.4"></a>

###### 3.1.11.8.4 Health-related Quality of Life and Patient-reported Outcomes

Not applicable.

<a id="heading-3.1.11.8.5"></a>

###### 3.1.11.8.5 Safety Results

<a id="topic-3.1.11.8.5-1"></a>

###### 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.”
> “The majority of treatment‐emergent AEs (128/197; 65%) were injection‐site reactions.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.8.5-2"></a>

###### 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).”
> “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.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="topic-3.1.11.8.5-3"></a>

###### 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.”
> “No significant dose effect was observed on platelet count in either single‐ or multiple‐dose cohorts.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.11.9"></a>

##### 3.1.11.9 Study Limitations

<a id="topic-3.1.11.9-1"></a>

###### 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.

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/); [Clinical Pharmacology in Drug Development (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13169179/)

<a id="topic-3.1.11.9-2"></a>

###### Limitation stated by the investigators

> “However, given the small sample size, continued assessment of liver chemistry is warranted to exclude the potential for drug‐induced liver injury.”

Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/)

<a id="heading-3.1.12"></a>

#### 3.1.12 B-Assured Hepatic Impairment Study

<a id="heading-3.1.12.1"></a>

##### 3.1.12.1 Objective

<a id="topic-3.1.12.1-1"></a>

###### Aim stated in the registry record

> “This is a Phase 1, open-label, parallel-group study to evaluate the pharmacokinetics of GSK3228836 in participants with Child-Pugh B (CP-B) cirrhosis (moderate hepatic impairment), Child-Pugh A (CP-A) cirrhosis (mild hepatic impairment) and participants with normal hepatic function as healthy control.”

Source: [ClinicalTrials.gov NCT04971928](https://clinicaltrials.gov/study/NCT04971928)

<a id="topic-3.1.12.1-2"></a>

###### Aim stated in the publication

> “B-Assured (GSK Study 205871; NCT04971928) was a phase 1, multicenter, open-label study conducted to assess the effect of HI on the PK and safety of bepirovirsen.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.2"></a>

##### 3.1.12.2 Location and Study Date

<a id="topic-3.1.12.2-1"></a>

###### Two United States centers, September 2021 to May 2022

> “This was a phase 1, nonrandomized, open-label, parallel-group study conducted between September 7, 2021 and May 12, 2022 in 2 centers in the United States (Texas Liver Institute, UT Health San Antonio, San Antonio, TX, USA and Orlando Clinical Research Center, Orlando, FL, USA).”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.2-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT04971928](https://clinicaltrials.gov/study/NCT04971928)

<a id="heading-3.1.12.3"></a>

##### 3.1.12.3 Study Design

<a id="topic-3.1.12.3-1"></a>

###### Two-part design with an interim decision rule

> “This study was planned to be conducted in 2 parts, allowing a planned interim analysis following Part 1 (Figure 1). Part 1 was planned to be conducted in participants with moderate HI and Part 2 in those with mild impairment.”
> “It was decided that if no preset (or predefined) difference in PKs (area under the concentration-time curve from time 0 to infinite time [AUC0-∞] and Cmax geometric mean ratio [GMR] within a 0.5-1.5 range) was found in participants with moderate HI compared with HPs (Part 1) during the interim analysis, the findings would be applied to participants with mild HI (Part 2), thus eliminating the need to progress to Part 2 and thereby ending the study.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.3-2"></a>

###### Matching of healthy participants

> “Participants with moderate and mild HI were to be matched with HPs by gender, age (±10 years), race, and total body weight (±25%) in a 1:1 ratio.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.4"></a>

##### 3.1.12.4 Eligibility Criteria

<a id="topic-3.1.12.4-1"></a>

###### Inclusion criteria and Child-Pugh classification

> “Participants were male or nonpregnant female, at least 18 years of age, body weight >50 kg and body mass index within the range 19-40 kg/m2 (inclusive) at the time of signing the informed consent.”
> “To be classified as having cirrhosis, participants must have a Child-Pugh score of 7-9 (B/moderate; this group was planned to include at least 1 participant with a Child-Pugh score of 7, a score of 8, and a score of 9) or 5-6 (A/mild; this group was planned to include at least 1 participant with a Child-Pugh score of 5 and a Child-Pugh score of 6). Bepirovirsen is in development for the treatment of chronic HBV infection, but there was no requirement for participants in this PK study to have chronic HBV infection.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.4-2"></a>

###### Key exclusion criteria

> “Key exclusion criteria were myocardial infarction or acute coronary syndrome, stroke, or transient ischemic attack within the 12 weeks prior to enrollment; diagnosed or suspected HCC, malignancy within the past 5 years except for specific cancers that were cured by surgical resection (eg, skin cancer); and participants under evaluation for possible malignancy, a history/potential of vasculitis or other diseases that may be associated with vasculitis condition (eg, systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, and mononeuritis multiplex), and unstable cardiac function or diabetes.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.5"></a>

##### 3.1.12.5 Treatment

<a id="topic-3.1.12.5-1"></a>

###### Single 300 mg subcutaneous dose

> “In Part 1 of the study, participants attended the clinical research unit on day 1 and received a single dose of bepirovirsen 300 mg (2.0 mL) subcutaneously (2 injections of 150 mg [1.0 mL] each) into the upper arm, thigh, or abdomen.”
> “Due to the time-invariant PK and lack of accumulation observed with bepirovirsen, a single-dose study was selected to reduce participant exposure to the study drug while maintaining the ability to assess the impact of HI on bepirovirsen PKs.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.6"></a>

##### 3.1.12.6 Study Outcomes

<a id="heading-3.1.12.6.1"></a>

###### 3.1.12.6.1 Rationale for Using Plasma AUC and Cmax as the Primary Endpoints

<a id="topic-3.1.12.6.1-1"></a>

###### Registered primary outcomes

> “Area under the concentration-time curve (AUC) from time zero (pre-dose) extrapolated to infinite time [AUC(0-infinity)]”
> “Maximum observed concentration (Cmax)”

Source: [ClinicalTrials.gov NCT04971928](https://clinicaltrials.gov/study/NCT04971928)

<a id="topic-3.1.12.6.1-2"></a>

###### Basis for the 0.5 to 1.5 geometric mean ratio thresholds

> “The criteria defined were based on the fold-difference between the lowest and highest doses tested in patients with chronic HBV infection (150 and 450 mg, respectively) compared with the therapeutic dose (300 mg).”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.6.1-3"></a>

###### Need for a hepatic impairment study in the target population

> “To our knowledge, no PK studies comparing healthy control and hepatically impaired participants have been conducted with ASOs, therefore it is difficult to predict bepirovirsen plasma exposure in this population. Hepatic impairment (HI) may alter the disposition of bepirovirsen by altering the drug concentration in plasma and liver and increasing free drug concentration, given that HI is associated with reductions in serum albumin concentrations.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.7"></a>

##### 3.1.12.7 Statistical Analysis Description

<a id="heading-3.1.12.7.1"></a>

###### 3.1.12.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.12.7.1-1"></a>

###### Planned sample size

> “The study aimed to enroll at least 24 participants, increased to approximately 48 participants if the study progressed to Part 2. A sample size of 12 PK-evaluable participants per group was selected based on the level of precision required for evaluation of PK parameters.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.7.1-2"></a>

###### Participants screened and dosed

> “A total of 30 participants were screened for the study, of whom 24 participants were assigned to receive active doses of bepirovirsen; 12 participants had moderate HI and 12 were matched healthy controls. No participants had chronic HBV infection.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.7.2"></a>

###### 3.1.12.7.2 Description of Analysis Sets

<a id="topic-3.1.12.7.2-1"></a>

###### Noncompartmental analysis and mixed effects model

> “Noncompartmental plasma PK analysis was conducted, and a mixed effects analysis of covariance model was created for each endpoint. In Part 1, a binary variable indicating whether a participant was a healthy volunteer was included as a fixed effect and a participant matching variable was included as a random effect.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.7.2-2"></a>

###### Protocol deviations and study populations

> “Two participants did not complete the day 8 visit and none of the endpoint assessments were performed; however, these deviations did not exclude the participants from any study population.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.8"></a>

##### 3.1.12.8 Results

<a id="heading-3.1.12.8.1"></a>

###### 3.1.12.8.1 Participant Disposition

<a id="topic-3.1.12.8.1-1"></a>

###### Screen failures and completion of part 1

> “Of the 6 participants who failed screening, 5 participants did not meet the inclusion/exclusion criteria for the study and 1 participant withdrew consent.”
> “Twenty-four participants (moderate HI, n = 12; HP, n = 12) received bepirovirsen and completed Part 1.”
> “Part 2 was omitted.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.8.2"></a>

###### 3.1.12.8.2 Baseline Characteristics

<a id="topic-3.1.12.8.2-1"></a>

###### 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)” |

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.8.2-2"></a>

###### Etiology of cirrhosis and concomitant medications

> “All the participants with moderate HI received medications before and during the study for management of their health conditions whereas only 1 participant in the healthy control group used concomitant medications. The most common concomitant medications in the group with HI were furosemide (n = 8), spironolactone (n = 7), and lactulose (n = 6). In the HI group, 6 participants had alcohol-related cirrhosis, 3 participants had hepatitis C cirrhosis, and 3 participants had nonalcoholic fatty liver disease cirrhosis at baseline.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.8.3"></a>

###### 3.1.12.8.3 Efficacy Results

<a id="topic-3.1.12.8.3-1"></a>

###### Geometric mean ratios, moderate hepatic impairment versus matched healthy controls

> “When a single dose of bepirovirsen was administered to participants with moderate HI, geometric least squares (LS) mean AUC0-∞ was lower than in matched healthy controls with geometric LS mean ratio (90% CI) of 0.69 (0.59, 0.82; Figure 2 and Table S3). The geometric LS mean Cmax was lower in participants with moderate HI compared with matched healthy controls with a geometric LS mean ratio (90% CI) of 0.67 (0.52, 0.85).”
> “The CL/F and Vz/F estimates were higher in participants with moderate HI with geometric LS mean ratios (90% CI) of 1.44 (1.22, 1.70) and 1.64 (1.24, 2.19) than in matched healthy controls, respectively (Figure 2 and Table S3).”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.8.3-2"></a>

###### Plasma PK parameters by group (geometric mean)

| Parameter | Moderate hepatic impairment (N = 12) | Matched healthy controls (N = 12) |
| --- | --- | --- |
| AUC0-∞ (h × μg/mL) | “75.1” | “108.9” |
| Cmax (μg/mL) | “6.57” | “9.83” |
| t1/2 (hour) | “232.2” | “204.9” |
| CL/F (L/h) | “4.00” | “2.75” |
| Vz/F (L) | “1338” | “814.2” |
| Tmax (hour), median (min, max) | “4.0 (3.0, 12.0)” | “5.1 (4.0, 8.1)” |

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.8.3-3"></a>

###### Decision not to proceed to part 2

> “Data from the planned interim analyses of Part 1 showed the GMRs of both total plasma AUC0-∞ and the Cmax of bepirovirsen between participants with moderate HI and matched healthy controls were between 0.5 and 1.5, therefore the study did not continue to Part 2; data from Part 1 are presented herein.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.8.3-4"></a>

###### Hepatic impairment statement in the prescribing information

> “There is a 33% reduction in Cmax and a 31% reduction in AUC0-∞ in participants with moderate hepatic impairment (Child-Pugh Class B) but without HBV infection when compared to participants with normal hepatic function.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.12.8.4"></a>

###### 3.1.12.8.4 Health-related Quality of Life and Patient-reported Outcomes

Not applicable.

<a id="heading-3.1.12.8.5"></a>

###### 3.1.12.8.5 Safety Results

<a id="topic-3.1.12.8.5-1"></a>

###### Adverse events and adverse events of special interest

> “A total of 6 (25%) participants experienced AEs, 3 from each group (Table S4). The most common AE was injection-site erythema, which was reported in 4 participants: 3 in the healthy control group and 1 in the HI group. All other AEs were reported in 1 participant each in the HI group. There were no deaths reported in the study and all AEs were mild in intensity and not serious.”
> “Five (21%) participants experienced injection-site reactions that were considered drug-related AEs by investigators. No clinically significant bleeding, ALT increases, vascular inflammation and complement activation, or renal injury were reported.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="topic-3.1.12.8.5-2"></a>

###### Immunogenicity

> “Two (8%) participants were positive for antibepirovirsen antibodies at baseline, of which 1 participant was positive for antibepirovirsen antibodies posttreatment. There were no PK or safety concerns identified in these participants.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.12.9"></a>

##### 3.1.12.9 Study Limitations

<a id="topic-3.1.12.9-1"></a>

###### 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.

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454); [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.12.9-2"></a>

###### Limitations stated by the investigators

> “The limitations to the present study included the fact that no participants had hepatitis B-induced cirrhosis; however, it is unclear whether the etiology of HI alters the drug PKs and disposition.”
> “Considering that the difference between participants with HI and HPs was not deemed clinically relevant, the outcome of unbound levels of bepirovirsen was not evaluated in this study.”

Source: [Noormohamed et al. (2024)](https://doi.org/10.1002/cpdd.1454)

<a id="heading-3.1.13"></a>

#### 3.1.13 B-Kind Renal Impairment Study

<a id="heading-3.1.13.1"></a>

##### 3.1.13.1 Objective

<a id="topic-3.1.13.1-1"></a>

###### Aim stated in the registry record

> “This is a 2-part study where all participants will receive bepirovirsen. The study will measure how much bepirovirsen from a single dose gets into the blood, and how long it stays in the blood. The purpose of the study is to understand if blood levels of bepirovirsen are different in adults with kidney disease compared to healthy adults who do not have kidney disease.”

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="heading-3.1.13.2"></a>

##### 3.1.13.2 Location and Study Date

<a id="topic-3.1.13.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="topic-3.1.13.2-2"></a>

###### Study locations in the registry record

> “This study has 3 locations”
> “Orlando, Florida, United States, 32809”
> “Tampa, Florida, United States, 33603”
> “San Antonio, Texas, United States, 78215”

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="heading-3.1.13.3"></a>

##### 3.1.13.3 Study Design

<a id="topic-3.1.13.3-1"></a>

###### Phase 1, open-label, single-dose, parallel-group design

> “A Phase 1, Open-Label, Single-Dose, Parallel Group, 2-Part Study to Evaluate the Pharmacokinetics of Bepirovirsen in Adult Participants With Severe or Moderate Renal Impairment Compared to Matched Healthy Control Participants”

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="topic-3.1.13.3-2"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="heading-3.1.13.4"></a>

##### 3.1.13.4 Eligibility Criteria

<a id="topic-3.1.13.4-1"></a>

###### Renal function groups

> “Severe renal impairment [estimated glomerular filtration rate (eGFR) adjusted for actual body surface area (BSA) less than 30 milliliters per minute (ml/min); Group 1] or moderate renal impairment [eGFR adjusted for actual BSA between 30 and 59 ml/min; Group 2], from any cause other than vasculitis or glomerulonephritis Additional inclusion criteria for healthy control participants with normal renal function (Group 3)”
> “Normal renal function (eGFR adjusted for actual BSA greater than or equal to 90 ml/min)”

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="topic-3.1.13.4-2"></a>

###### Other inclusion and exclusion criteria

> “Age 18 to 80 years, inclusive”
> “Body weight greater than or equal to 50 kilograms (kg) and body mass index (BMI) within the range 19 to 40 kilograms per square meter (kg/m^2).”
> “A positive blood test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).”
> “On dialysis or likely to require dialysis during the study.”
> “History of renal transplantation or anticipated renal transplant during the study.”

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="heading-3.1.13.5"></a>

##### 3.1.13.5 Treatment

<a id="topic-3.1.13.5-1"></a>

###### Single dose of bepirovirsen in each group

> “Participants with severe renal impairment will receive Bepirovirsen.”
> “Participants with moderate renal impairment will receive Bepirovirsen.”
> “Healthy control participants will receive Bepirovirsen.”

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="heading-3.1.13.6"></a>

##### 3.1.13.6 Study Outcomes

<a id="heading-3.1.13.6.1"></a>

###### 3.1.13.6.1 Rationale for Using Plasma AUC and Cmax as the Primary Endpoints

<a id="topic-3.1.13.6.1-1"></a>

###### Registered primary and secondary outcomes

> “Plasma Area Under the Concentration Time Curve From Time Zero (Pre-Dose) Extrapolated to Infinite Time [AUC(0-∞)] of Bepirovirsen”
> “Maximum Observed Concentration (Cmax) of Bepirovirsen”
> “Apparent Clearance (CL/F) of Bepirovirsen”
> “Apparent Terminal Phase Half-life (t1/2) of Bepirovirsen”

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="topic-3.1.13.6.1-2"></a>

###### Renal impairment data gap in the prescribing information

> “Insufficient data are available on the safety of HIBSAGO in patients with moderate or severe renal impairment or end stage renal disease (eGFR less than or equal to 59 mL/min/1.73m2).”
> “Renal Impairment: Bepirovirsen pharmacokinetics were similar between patients with CHB with an eGFR 60 to 89 mL/min/1.73m2 compared to patients with an eGFR ≥90 mL/min/1.73 m2. Insufficient data are available in patients with moderate or severe renal impairment.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.13.7"></a>

##### 3.1.13.7 Statistical Analysis Description

<a id="heading-3.1.13.7.1"></a>

###### 3.1.13.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.13.7.1-1"></a>

###### Enrollment in the registry record

| Field | Registry entry |
| --- | --- |
| Enrollment (actual) | “32” |

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356)

<a id="heading-3.1.13.7.2"></a>

###### 3.1.13.7.2 Description of Analysis Sets

No evidence found.

<a id="heading-3.1.13.8"></a>

##### 3.1.13.8 Results

<a id="heading-3.1.13.8.1"></a>

###### 3.1.13.8.1 Participant Disposition

No evidence found.

<a id="heading-3.1.13.8.2"></a>

###### 3.1.13.8.2 Baseline Characteristics

No evidence found.

<a id="heading-3.1.13.8.3"></a>

###### 3.1.13.8.3 Efficacy Results

No evidence found.

<a id="heading-3.1.13.8.4"></a>

###### 3.1.13.8.4 Health-related Quality of Life and Patient-reported Outcomes

Not applicable.

<a id="heading-3.1.13.8.5"></a>

###### 3.1.13.8.5 Safety Results

No evidence found.

<a id="heading-3.1.13.9"></a>

##### 3.1.13.9 Study Limitations

<a id="topic-3.1.13.9-1"></a>

###### 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.

Source: [ClinicalTrials.gov NCT07168356](https://clinicaltrials.gov/study/NCT07168356); [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.14"></a>

#### 3.1.14 Study 219239 Relative Bioavailability of Vial and Prefilled Syringe

<a id="heading-3.1.14.1"></a>

##### 3.1.14.1 Objective

<a id="topic-3.1.14.1-1"></a>

###### Aim stated in the registry record

> “The aim of this study is to provide relative bioavailability data to support the transition from the vial presentation of bepirovirsen, to a ready-to-use liquid in a PFS SSD when both are given by a health care professional. The study will also assess self-administration using the PFS SDD, and the safety and tolerability of bepirovirsen.”

Source: [ClinicalTrials.gov NCT06058390](https://clinicaltrials.gov/study/NCT06058390)

<a id="topic-3.1.14.1-2"></a>

###### 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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="heading-3.1.14.2"></a>

##### 3.1.14.2 Location and Study Date

<a id="topic-3.1.14.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT06058390](https://clinicaltrials.gov/study/NCT06058390)

<a id="topic-3.1.14.2-2"></a>

###### Study locations in the registry record

> “This study has 2 locations”
> “Las Vegas, Nevada, United States, 89113”
> “Austin, Texas, United States, 78744”

Source: [ClinicalTrials.gov NCT06058390](https://clinicaltrials.gov/study/NCT06058390)

<a id="heading-3.1.14.3"></a>

##### 3.1.14.3 Study Design

<a id="topic-3.1.14.3-1"></a>

###### 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).”
> “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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.3-2"></a>

###### Pharmacokinetic sampling schedule

> “Pharmacokinetic (PK) samples were collected from all participants pre‐dose and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 168, 336, 672, 1008, and 1512 h post‐dose.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.3-3"></a>

###### Healthy participants as the study population

> “Conducting the study in healthy participants mitigates the recruitment and patient burden limitations with administering a single dose of bepirovirsen to CHB patients.”

Source: [GSK 219239 protocol (2023)](https://cdn.clinicaltrials.gov/large-docs/90/NCT06058390/Prot_000.pdf)

<a id="heading-3.1.14.4"></a>

##### 3.1.14.4 Eligibility Criteria

<a id="topic-3.1.14.4-1"></a>

###### 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.”
> “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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="heading-3.1.14.5"></a>

##### 3.1.14.5 Treatment

<a id="topic-3.1.14.5-1"></a>

###### 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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.5-2"></a>

###### 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.”
> “The formulation of bepirovirsen is identical between the vial and the PFS SSD.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="heading-3.1.14.6"></a>

##### 3.1.14.6 Study Outcomes

<a id="heading-3.1.14.6.1"></a>

###### 3.1.14.6.1 Rationale for Using Relative Bioavailability (Plasma Cmax and AUC) as the Primary Endpoint

<a id="topic-3.1.14.6.1-1"></a>

###### 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.”
> “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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.6.1-2"></a>

###### Purpose of the bioavailability comparison

> “The aim of this study is to provide relative bioavailability data to support the transition from the vial presentation of bepirovirsen, which is currently under investigation in the Phase 3 trials, to a ready-to-use liquid in a PFS fitted with an SSD.”

Source: [GSK 219239 protocol (2023)](https://cdn.clinicaltrials.gov/large-docs/90/NCT06058390/Prot_000.pdf)

<a id="heading-3.1.14.7"></a>

##### 3.1.14.7 Statistical Analysis Description

<a id="heading-3.1.14.7.1"></a>

###### 3.1.14.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.14.7.1-1"></a>

###### Participants screened, enrolled, and analyzed

> “A total of 359 participants were screened and 160 participants enrolled in the study.”
> “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).”
> “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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.7.1-2"></a>

###### Planned sample size

> “The planned sample size was 160 participants.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="heading-3.1.14.7.2"></a>

###### 3.1.14.7.2 Description of Analysis Sets

<a id="topic-3.1.14.7.2-1"></a>

###### Analysis sets in the registry results

> “All-cause mortality, SAEs and non-SAEs were reported for Safety Population which included participants who received study intervention. One participant from Enrolled Population (N=160) did not receive study intervention, hence was not included in Safety Population (N=159).”
> “Pharmacokinetic (PK) Parameter Population included all participants in the PK concentration Population for whom valid and evaluable plasma PK parameters were derived.”

Source: [ClinicalTrials.gov NCT06058390](https://clinicaltrials.gov/study/NCT06058390?tab=results)

<a id="topic-3.1.14.7.2-2"></a>

###### 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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="heading-3.1.14.8"></a>

##### 3.1.14.8 Results

<a id="heading-3.1.14.8.1"></a>

###### 3.1.14.8.1 Participant Disposition

<a id="topic-3.1.14.8.1-1"></a>

###### Participant flow in the registry results

| Milestone | Vial by HCP | PFS SSD by HCP | PFS SSD self-administered after training | PFS SSD self-administered without training |
| --- | --- | --- | --- | --- |
| Started | “46” | “49” | “32” | “33” |
| Completed | “46” | “49” | “30” | “30” |
| Not completed | “0” | “0” | “2” | “3” |

Source: [ClinicalTrials.gov NCT06058390](https://clinicaltrials.gov/study/NCT06058390?tab=results)

<a id="topic-3.1.14.8.1-2"></a>

###### 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.”
> “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).”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="heading-3.1.14.8.2"></a>

###### 3.1.14.8.2 Baseline Characteristics

<a id="topic-3.1.14.8.2-1"></a>

###### 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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="heading-3.1.14.8.3"></a>

###### 3.1.14.8.3 Efficacy Results

<a id="topic-3.1.14.8.3-1"></a>

###### 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).”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.8.3-2"></a>

###### 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).”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.8.3-3"></a>

###### 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)” | “10,242.48 (39.54)” | “10,391.83 (42.70)” | “9516.35 (47.41)” |
| AUC(0‐inf) (ng·h/mL) | “111,843.70 (32.93)” | “119,271.61 (29.70)” | “119,080.46 (26.28)” | “112,338.58 (35.01)” |

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.8.3-4"></a>

###### 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).”
> “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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.8.3-5"></a>

###### Registry results: 90% confidence intervals for the primary comparison

> “0.91 to 1.14”
> “0.96 to 1.15”

Source: [ClinicalTrials.gov NCT06058390](https://clinicaltrials.gov/study/NCT06058390?tab=results)

<a id="heading-3.1.14.8.4"></a>

###### 3.1.14.8.4 Health-related Quality of Life and Patient-reported Outcomes

Not applicable.

<a id="heading-3.1.14.8.5"></a>

###### 3.1.14.8.5 Safety Results

<a id="topic-3.1.14.8.5-1"></a>

###### 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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.8.5-2"></a>

###### Adverse events reported in at least 3% of participants overall

| Preferred term | Vial by HCP (N = 46) | PFS SSD by HCP (N = 49) | PFS SSD self-administered with training (N = 32) | PFS SSD self-administered without training (N = 32) | Total (N = 159) |
| --- | --- | --- | --- | --- | --- |
| Any event | “45 (98%)” | “43 (88%)” | “32 (100%)” | “30 (94%)” | “150 (94%)” |
| Injection site erythema | “35 (76%)” | “37 (76%)” | “30 (94%)” | “30 (94%)” | “132 (83%)” |
| Injection site swelling | “21 (46%)” | “24 (49%)” | “14 (44%)” | “19 (59%)” | “78 (49%)” |
| Injection site pain | “23 (50%)” | “22 (45%)” | “10 (31%)” | “12 (38%)” | “67 (42%)” |
| Injection site pruritus | “8 (17%)” | “11 (22%)” | “9 (28%)” | “13 (41%)” | “41 (26%)” |
| Headache | “12 (26%)” | “5 (10%)” | “5 (16%)” | “7 (22%)” | “29 (18%)” |
| Nausea | “3 (7%)” | “3 (6%)” | “2 (6%)” | “1 (3%)” | “9 (6%)” |
| Myalgia | “5 (11%)” | “1 (2%)” | “1 (3%)” | “1 (3%)” | “8 (5%)” |
| Pyrexia | “3 (7%)” | “2 (4%)” | “1 (3%)” | “1 (3%)” | “7 (4%)” |

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.8.5-3"></a>

###### 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%]).”
> “AESIs related to thrombocytopenia were reported by 18% (29/159) of participants with no clear difference between treatment groups”
> “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.”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.8.5-4"></a>

###### 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%)” |

Source: [ClinicalTrials.gov NCT06058390](https://clinicaltrials.gov/study/NCT06058390?tab=results)

<a id="heading-3.1.14.9"></a>

##### 3.1.14.9 Study Limitations

<a id="topic-3.1.14.9-1"></a>

###### 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.

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="topic-3.1.14.9-2"></a>

###### 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.”
> “It is unclear from the data whether the difference in exposure by injection site is real or due to variability.”
> “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).”

Source: [Youssef et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12856967/)

<a id="heading-3.1.15"></a>

#### 3.1.15 Study 205873 Thorough QT Study

<a id="heading-3.1.15.1"></a>

##### 3.1.15.1 Objective

<a id="topic-3.1.15.1-1"></a>

###### Aim stated in the registry record

> “This study will evaluate the effect of a single dose of bepirovirsen on the QT interval corrected by Fridericia's formula (QTcF) as compared to placebo. The data generated will be used to model the relationship between bepirovirsen concentration and QTcF.”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767)

<a id="topic-3.1.15.1-2"></a>

###### Purpose stated in the protocol

> “This study will be conducted to evaluate the effect of bepirovirsen on cardiac repolarization and data generated will be used to conduct concentration-QTcF analyses for bepirovirsen.”
> “The exposure data collected from supratherapeutic single doses of bepirovirsen will be used to provide confidence that the risk of QT/QTcF interval prolongation at the therapeutic dose of 300 mg is low, along with the collected ECG measurements in the Phase 1 and 2a studies”

Source: [GSK 205873 protocol (2024)](https://cdn.clinicaltrials.gov/large-docs/67/NCT06422767/Prot_000.pdf)

<a id="heading-3.1.15.2"></a>

##### 3.1.15.2 Location and Study Date

<a id="topic-3.1.15.2-1"></a>

###### 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” |

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767)

<a id="topic-3.1.15.2-2"></a>

###### Study location in the registry record

> “This study has 1 location”
> “Austin, Texas, United States, 78744 -1645”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767)

<a id="heading-3.1.15.3"></a>

##### 3.1.15.3 Study Design

<a id="topic-3.1.15.3-1"></a>

###### Randomized, double-blind, placebo-controlled, parallel-group design

> “A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, Parallel Group Study to Evaluate the Effect of Bepirovirsen on Cardiac Conduction as Assessed by 12-lead Electrocardiogram in Healthy Volunteers”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767)

<a id="topic-3.1.15.3-2"></a>

###### Planned 1:1 randomization and dose reduction under protocol amendment 2

> “A total of approximately 46 participants will be enrolled and randomized 1:1 into parallel arms to receive a single supratherapeutic dose of bepirovirsen,”
> “participants dosed, 2 experienced tolerability issues related to systemic AEs”
> “A decision was made not to dose any further participants with bepirovirsen”

Source: [GSK 205873 protocol (2024)](https://cdn.clinicaltrials.gov/large-docs/67/NCT06422767/Prot_000.pdf)

<a id="topic-3.1.15.3-3"></a>

###### Supratherapeutic doses stated in the prescribing information

> “At supratherapeutic doses of 450 or 600 mg (1.5 and 2 times the recommended dosage) of HIBSAGO, clinically significant QTc interval prolongation was not observed.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.15.4"></a>

##### 3.1.15.4 Eligibility Criteria

<a id="topic-3.1.15.4-1"></a>

###### Key inclusion criteria

> “Participant must be 18 to 55 years of age inclusive, at the time of signing the informed consent.”
> “Participants who are overtly healthy as determined by medical evaluation, including medical history, physical examination, laboratory tests, electrocardiogram (ECG) and vital signs.”
> “Body weight greater than equal to (>=) 50 Kilograms (kg) and Body mass index (BMI) within the range 19-32 Kilograms per square meter (kg/m^2) (inclusive).”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767)

<a id="topic-3.1.15.4-2"></a>

###### Key exclusion criteria

> “Known history of heart disease, including ischemic heart disease, cardiomyopathy, clinically significant cardiac arrhythmias, clinically significant valvular disease, or hypertensive heart disease.”
> “Positive test results for Hepatitis B surface antigen (HBsAg), hepatitis C antibody or hepatitis C RNA at screening or within 3 months prior to first dose of study intervention.”
> “Prior treatment with any oligonucleotide or small interfering Ribonucleic acid (RNA) (siRNA) within 12 months before dosing.”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767)

<a id="heading-3.1.15.5"></a>

##### 3.1.15.5 Treatment

<a id="topic-3.1.15.5-1"></a>

###### 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.” |

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767)

<a id="heading-3.1.15.6"></a>

##### 3.1.15.6 Study Outcomes

<a id="heading-3.1.15.6.1"></a>

###### 3.1.15.6.1 Rationale for Using Placebo-corrected Change From Baseline in QTcF as the Primary Endpoint

<a id="topic-3.1.15.6.1-1"></a>

###### Registered primary outcome and concentration-QTc method

> “Geometric mean and 90 percent (%) Confidence Interval (CI) of predicted CFB QTcF adjusted for placebo at Cmax following supratherapeutic single doses of Bepirovirsen was presented using concentration QTc (C-QTc) analysis using exposure-response modelling.”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767)

<a id="topic-3.1.15.6.1-2"></a>

###### Regulatory basis in the ICH E14 guidance

> “The ICH E14 guidance, as adopted in the US FDA Guidance for Industry, E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs [Department of Health and Human Services, 2005], emphasizes the need to obtain clear and robust data through studies that assess the effect of new chemical entities on ECG parameters.”
> “A supratherapeutic dose is defined as a dose that provides exposures (mean Cmax) exceeding the high clinical scenario [ICH E14/S7B Questions and Answers 5.1, 2022].”
> “The primary endpoint is the change from baseline in Fridericia heart-rate-corrected QT interval (QTcF) under bepirovirsen exposure following a supratherapeutic single dose.”

Source: [GSK 205873 protocol (2024)](https://cdn.clinicaltrials.gov/large-docs/67/NCT06422767/Prot_000.pdf)

<a id="topic-3.1.15.6.1-3"></a>

###### Hypothesis threshold of 10 msec

> “For the primary estimand, the following 1-sided hypothesis is planned to be tested for QT prolongation following the supratherapeutic single dose of bepirovirsen against a predefined threshold of 10 msec using the C-QTcF analysis:”

Source: [GSK 205873 protocol (2024)](https://cdn.clinicaltrials.gov/large-docs/67/NCT06422767/Prot_000.pdf)

<a id="heading-3.1.15.7"></a>

##### 3.1.15.7 Statistical Analysis Description

<a id="heading-3.1.15.7.1"></a>

###### 3.1.15.7.1 Number of Participants (Planned and Analyzed)

<a id="topic-3.1.15.7.1-1"></a>

###### Planned sample size and power

> “A sample size of approximately 46 participants with 1:1 randomization is chosen to obtain 42 evaluable participants to complete the study under the original design of receiving a single dose of either placebo or”
> “A size of 42 evaluable participants with concentration and ΔQTcF measured around Cmax provides at least 90% power to exclude that active drug caused more than a 10-msec QTcF effect at clinically relevant plasma levels”

Source: [GSK 205873 protocol (2024)](https://cdn.clinicaltrials.gov/large-docs/67/NCT06422767/Prot_000.pdf)

<a id="topic-3.1.15.7.1-2"></a>

###### Enrollment and participants analyzed for the primary outcome

| Arm | Started | Analyzed for the primary outcome |
| --- | --- | --- |
| Bepirovirsen, four injections | “5” | “5” |
| Placebo, four injections | “5” | Not reported |
| Bepirovirsen, three injections | “18” | “18” |
| Placebo, three injections | “18” | Not reported |

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

<a id="heading-3.1.15.7.2"></a>

###### 3.1.15.7.2 Description of Analysis Sets

<a id="topic-3.1.15.7.2-1"></a>

###### Analysis sets defined in the protocol

> “All participants in the safety population with a valid ΔQTcF value (measurements at baseline as well as on-treatment with at least 1 post-dose time point).”
> “All participants in the Safety Set who had at least 1 non-missing PK assessment (NQ values will be considered as non-missing values).”

Source: [GSK 205873 protocol (2024)](https://cdn.clinicaltrials.gov/large-docs/67/NCT06422767/Prot_000.pdf)

<a id="topic-3.1.15.7.2-2"></a>

###### Population for the primary analysis in the registry results

> “Analysis was performed on pharmacokinetic (PK)/QTcF set that included all participants who were in both the QT/QTcF and PK populations with at least 1 pair of post dose PK and CFB QTcF data from the same time point as well as participants in the QT/QTcF population who received placebo.”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

<a id="heading-3.1.15.8"></a>

##### 3.1.15.8 Results

<a id="heading-3.1.15.8.1"></a>

###### 3.1.15.8.1 Participant Disposition

<a id="topic-3.1.15.8.1-1"></a>

###### Participant flow in the registry results

| Milestone | Bepirovirsen, four injections | Placebo, four injections | Bepirovirsen, three injections | Placebo, three injections |
| --- | --- | --- | --- | --- |
| Started | “5” | “5” | “18” | “18” |
| Completed | “5” | “5” | “18” | “18” |
| Not completed | “0” | “0” | “0” | “0” |

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

<a id="heading-3.1.15.8.2"></a>

###### 3.1.15.8.2 Baseline Characteristics

<a id="topic-3.1.15.8.2-1"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

<a id="heading-3.1.15.8.3"></a>

###### 3.1.15.8.3 Efficacy Results

<a id="topic-3.1.15.8.3-1"></a>

###### 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)” |

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

<a id="topic-3.1.15.8.3-2"></a>

###### Bepirovirsen plasma PK parameters (geometric mean, geometric CV%)

| Parameter | Bepirovirsen, four injections (n = 5) | Bepirovirsen, three injections (n = 18) |
| --- | --- | --- |
| Cmax (µg/mL) | “16.88” | “15.77” |
| AUC(0-24) (h·µg/mL) | “204.01” | “169.80” |
| AUC(0-t) (h·µg/mL) | “215.04” | “177.21” |
| Tmax (h) | “4.10” | “3.38” |

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

<a id="topic-3.1.15.8.3-3"></a>

###### AUC extrapolated to infinity not calculated

> “Data were not analyzed for AUC(0-infinity) as there were not enough data points collected for a terminal slope required to calculate AUC(0-infinity).”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

<a id="topic-3.1.15.8.3-4"></a>

###### QTc conclusion in the prescribing information

> “At supratherapeutic doses of 450 or 600 mg (1.5 and 2 times the recommended dosage) of HIBSAGO, clinically significant QTc interval prolongation was not observed.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="heading-3.1.15.8.4"></a>

###### 3.1.15.8.4 Health-related Quality of Life and Patient-reported Outcomes

Not applicable.

<a id="heading-3.1.15.8.5"></a>

###### 3.1.15.8.5 Safety Results

<a id="topic-3.1.15.8.5-1"></a>

###### 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%)” |

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

<a id="topic-3.1.15.8.5-2"></a>

###### Tolerability at 600 mg

> “Single doses of HIBSAGO 600 mg (2 times the recommended dose) were administered subcutaneously in a clinical trial to 5 healthy adults. Two participants developed tolerability issues at this dose, with symptoms including headache, nausea, vomiting, myalgia, and dizziness which lasted 24 to 48 hours despite symptomatic treatment.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.15.8.5-3"></a>

###### Systemic symptoms described in the protocol

> “Two of the 10 randomized participants exhibited a variety of symptoms of mild and moderate severity, including headache, nausea, vomiting, myalgia, and dizziness. These symptoms were associated with low-grade fever and/or elevated CRP, suggestive of a systemic inflammatory response. These participants experienced discomfort for up to 48 hours after dosing, despite symptomatic treatment.”

Source: [GSK 205873 protocol (2024)](https://cdn.clinicaltrials.gov/large-docs/67/NCT06422767/Prot_000.pdf)

<a id="heading-3.1.15.9"></a>

##### 3.1.15.9 Study Limitations

<a id="topic-3.1.15.9-1"></a>

###### 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.

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767); [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results); [GSK 205873 protocol (2024)](https://cdn.clinicaltrials.gov/large-docs/67/NCT06422767/Prot_000.pdf); [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-3.1.15.9-2"></a>

###### Limitations and caveats in the registry results

> “Protocol specified AUC(0-inf) could not be calculated due to missing half-life estimates arising from the short period for PK sampling (not enough data points collected for a terminal slope required to calculate AUC[0-infinity]).”

Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results)

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