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

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

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

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

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

Study dates and status in the ClinicalTrials.gov record

“Study Start (Actual) 2022-12-06” (opens the source at this quote in a new tab)
“Primary Completion (Actual) 2025-11-03” (opens the source at this quote in a new tab)
“Study Completion (Actual) 2026-04-13” (opens the source at this quote in a new tab)
“First Posted 2022-11-30” (opens the source at this quote in a new tab)
“Last Update Posted 2026-07-08” (opens the source at this quote in a new tab)
“Completed” (opens the source at this quote in a new tab)
“No Results Posted” (opens the source at this quote in a new tab)

Number of locations in the ClinicalTrials.gov record

“This study has 171 locations” (opens the source at this quote in a new tab)

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”

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” (opens the source at this quote in a new tab)
“Start of trial 17/01/2023” (opens the source at this quote in a new tab)
“End of trial 20/10/2025” (opens the source at this quote in a new tab)
“Global end of trial 13/04/2026” (opens the source at this quote in a new tab)
“Estimated recruitment start date in EU/EEA: 21/12/2022” (opens the source at this quote in a new tab)

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” (opens the source at this quote in a new tab)
“Trial being conducted both within and outside the EEA Yes” (opens the source at this quote in a new tab)
“Date of Competent Authority Decision 2023-03-14” (opens the source at this quote in a new tab)
“Date of Ethics Committee Opinion 2023-02-09” (opens the source at this quote in a new tab)

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

Trial start in the company pipeline appendix

“Trial start: Q4 2022” (opens the source at this quote in a new tab)

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

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

Design details in the ClinicalTrials.gov record

Field	Registry value
Phase	“Phase 3”
Primary purpose	“Treatment”
Allocation	“Randomized”
Interventional model	“Parallel Assignment”
Model description	“This is a multicenter, randomized, double-blind, placebo-controlled study.”
Masking	“Quadruple”
Masking description	“This will be a double blinded study in which investigators/site staff and the Sponsor will remain blinded to treatment assignment.”

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

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

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]).” (opens the prescribing information at this quote)
“The randomization was stratified by HBsAg levels at baseline (HBsAg ≤ 1,000 IU/mL or >1,000 IU/mL to ≤3,000 IU/mL).” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)
“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” (opens the prescribing information at this quote)
“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.” (opens the prescribing information at this quote)
“Blips were defined as transiently quantifiable HBV DNA (≥LLOQ) or detected HBsAg at a single visit.” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)

Replicate double-blind design in the primary publication

“In two replicate, double-blind trials (B-Well 1 and B-Well 2), we randomly assigned adults with noncirrhotic chronic HBV infection in a 2:1 ratio to receive subcutaneous bepirovirsen (at a weekly dose of 300 mg) or placebo for 24 weeks.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“Eligible patients discontinued NA therapy at 48 weeks.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

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

“Therapeutic confirmatory (Phase III) Yes” (opens the source at this quote in a new tab)
“Placebo Yes” (opens the source at this quote in a new tab)
“Number of treatment arms in the trial 2” (opens the source at this quote in a new tab)
“Trial has a data monitoring committee Yes” (opens the source at this quote in a new tab)

Design of both B-Well trials stated by the company

“The B-Well 1 and B-Well 2 trials are global multi-centre, randomised, double-blind, placebo-controlled trials conducted in 29 countries.” (opens the source at this quote in a new tab)

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.” (opens the prescribing information at this quote)
“Participants could be either HBeAg-positive or HBeAg-negative at baseline.” (opens the prescribing information at this quote)
“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.” (opens the prescribing information at this quote)

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.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

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.” (opens the source at this quote in a new tab)
“Plasma or serum HBsAg concentration >100 IU/mL, but no greater than ≤3000 IU/mL.” (opens the source at this quote in a new tab)
“Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.” (opens the source at this quote in a new tab)
“Alanine aminotransferase (ALT) ≤2 × upper limit of normal (ULN).” (opens the source at this quote in a new tab)
“Participants who are willing and able to cease their NA treatment in accordance with the protocol.” (opens the source at this quote in a new tab)
“Ages Eligible for Study 18 Years and older” (opens the source at this quote in a new tab)
“Accepts Healthy Volunteers No” (opens the source at this quote in a new tab)

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.” (opens the source at this quote in a new tab)
“History of or suspected liver cirrhosis and/or evidence of cirrhosis.” (opens the source at this quote in a new tab)
“Diagnosed or suspected hepatocellular carcinoma.” (opens the source at this quote in a new tab)
“History of malignancy within the past 5 years except for specific cancers that are cured by surgical resection (e.g., skin cancer).” (opens the source at this quote in a new tab)
“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).” (opens the source at this quote in a new tab)
“History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).” (opens the source at this quote in a new tab)
“History of alcohol or drug abuse/dependence.” (opens the source at this quote in a new tab)

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.” (opens the source at this quote in a new tab)
“Currently taking, or has taken within 12 months of Screening, any interferon containing therapy.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“Prior treatment with any oligonucleotide or siRNA within 12 months prior to the first dosing day.” (opens the source at this quote in a new tab)
“Prior treatment with bepirovirsen.” (opens the source at this quote in a new tab)

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” (opens the source at this quote in a new tab)
“Both APRI >2 and FibroSure/FibroTest result >0.7” (opens the source at this quote in a new tab)
“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” (opens the source at this quote in a new tab)
“Liver biopsy (i.e., Metavir Score F4)” (opens the source at this quote in a new tab)
“Liver stiffness >12 kPa” (opens the source at this quote in a new tab)

Other exclusion criteria in the EU Clinical Trials Register record

“Hepatitis D virus defined as HDV antibody positive” (opens the source at this quote in a new tab)
“Diagnosed or suspected hepatocellular carcinoma as evidenced by the following” (opens the source at this quote in a new tab)
“Alpha-fetoprotein concentration ≥200 ng/mL” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“Fridericia’s QT correction formula (QTcF) ≥450 msec” (opens the source at this quote in a new tab)
“At least 18 years of age at the time of signing the informed consent” (opens the source at this quote in a new tab)

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.” (opens the prescribing information at this quote)
“Each dose of HIBSAGO was administered as two 150 mg subcutaneous injections into the abdomen, thigh, and/or outer area of upper arms.” (opens the prescribing information at this quote)
“From Week 25 to 48, participants continued to receive their NrtI therapy without HIBSAGO or placebo.” (opens the prescribing information at this quote)

Dose and duration in the primary publication

“subcutaneous bepirovirsen (at a weekly dose of 300 mg) or placebo for 24 weeks” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

Arms and interventions in the ClinicalTrials.gov record

Arm	Registry value
Experimental arm	“Experimental: Bepirovirsen”; “Bepirovirsen will be administered.”
Placebo arm	“Placebo Comparator: Placebo”; “Matching placebo will be administered.”

Treatment arms in the company pipeline appendix

“Arm A: bepirovirsen for 24 weeks” (opens the source at this quote in a new tab)
“Arm B: placebo” (opens the source at this quote in a new tab)

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.”

Registered primary outcome measure in the ClinicalTrials.gov record

“Number of participants achieving functional cure (FC) with baseline HBsAg ≤3000 IU/mL” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“Up to 72 weeks” (opens the source at this quote in a new tab)

Registered secondary outcome measures in the ClinicalTrials.gov record

“Number of participants achieving FC with baseline HBsAg ≤1000 IU/mL” (opens the source at this quote in a new tab)
“Number of participants achieving sustained suppression of HBV DNA (<LLOQ) with baseline HBsAg ≤3000 IU/mL” (opens the source at this quote in a new tab)
“Number of participants achieving sustained suppression of HBV DNA (<LLOQ) with baseline HBsAg ≤1000 IU/mL” (opens the source at this quote in a new tab)

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” (opens the source at this quote in a new tab)
“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” (opens the source at this quote in a new tab)
“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” (opens the source at this quote in a new tab)
“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” (opens the source at this quote in a new tab)
“Timepoint(s) of evaluation of this end point Week 72” (opens the source at this quote in a new tab)

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.” (opens the prescribing information at this quote)
“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.” (opens the prescribing information at this quote)
“The first key secondary endpoint was assessed by applying the same criteria to participants with baseline HBsAg ≤1,000 IU/mL.” (opens the prescribing information at this quote)
“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.” (opens the prescribing information at this quote)
“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.” (opens the prescribing information at this quote)
“Blips in the Week 72 analysis window were permitted for the primary and key secondary endpoint analyses.” (opens the prescribing information at this quote)

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

Functional cure definition and primary outcome in the primary publication

“Treatment with bepirovirsen, an antisense oligonucleotide targeting hepatitis B virus (HBV) transcripts, has the potential to result in a functional cure, defined by at least 24 weeks of a sustained HBV DNA level below the lower limit of quantification (LLOQ) and hepatitis B surface antigen (HBsAg) loss after fixed-duration therapy.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“The primary outcome was a functional cure at week 72.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

Functional cure as the preferred primary endpoint: AASLD-EASL treatment endpoints conference

“Of all these surrogate endpoints, HBsAg loss is considered to be the most relevant because HBsAg seroclearance is associated with sustained off-treatment improvement in clinical outcomes.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Moreover, HBsAg seroclearance is easy to measure with standardized and widely available assays.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The recommended endpoint of novel therapy is functional cure defined as HBsAg loss using a conventional assay for detection of HBsAg (limit of detection 0.05 IU/mL) and HBV DNA below the lower limit of quantification (i.e. < 10 IU/ml) at 24 weeks off-therapy.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Clinical endpoints are unfeasible as trial endpoints: AASLD-EASL treatment endpoints conference

“These clinical endpoints however typically develop over decades and are therefore unfeasible to be used as primary therapeutic endpoints for clinical trials of new investigational agents.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Although long-term sustained off-treatment HBV DNA suppression is associated with similar improvements in clinical outcomes as HBsAg loss, in patients with cirrhosis, it is not reliably durable, and there is a 15-40% lifetime chance of disease reactivation.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Nucleos(t)ide analogue withdrawal in trial control arms: AASLD-EASL treatment endpoints conference

“If off-treatment response is a primary endpoint, then NA should be withdrawn from both active treatment and control arms but only if stringent predetermined criteria based on HBsAg levels and other parameters are met to ensure safety.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

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

“HBsAg loss is considered the best predictor of sustained remission off-treatment” (opens the source at this quote in a new tab)
“To evaluate the primary efficacy outcome of sustained HBV DNA suppression off-treatment with HBsAg loss” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“It is expected that few subjects would meet such criteria on the placebo arm.” (opens the source at this quote in a new tab)
“For CHB, HBV DNA suppression with or without HBsAg loss is considered a validated surrogate endpoint that has been demonstrated to predict clinical outcomes” (opens the source at this quote in a new tab)

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".” (opens the source at this quote in a new tab)
“HBsAg loss is the ultimate goal of therapy.” (opens the source at this quote in a new tab)

Functional cure as the optimal endpoint for new therapies: bepirovirsen phase 2b design report

“Recently, functional cure, defined as durable hepatitis B surface antigen (HBsAg) loss with or without HBsAg seroconversion and undetectable HBV DNA, has been accepted as the optimal endpoint for new HBV therapies” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Functional cure is rare (≤ 5%) with NA therapy” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Planned number of participants in the EU Clinical Trials Register record

“In the EEA 191” (opens the source at this quote in a new tab)
“In the whole clinical trial 900” (opens the source at this quote in a new tab)
“Number of subjects for this age range: 738” (opens the source at this quote in a new tab)
“Number of subjects for this age range: 162” (opens the source at this quote in a new tab)

Actual enrollment in the ClinicalTrials.gov record

“Enrollment (Actual) 857” (opens the source at this quote in a new tab)

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

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.” (opens the prescribing information at this quote)
“In the FAS of 856 participants who received at least one dose of HIBSAGO or placebo” (opens the prescribing information at this quote)

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”

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)” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

Pooled B-Well 1 and B-Well 2 results: 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.” (opens the source at this quote in a new tab)

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.” (opens the prescribing information at this quote)

Full analysis set used for efficacy

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

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.” (opens the prescribing information at this quote)
“Based on two-sided p-value (exact Cochran-Mantel Haenszel).” (opens the prescribing information at this quote)

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

“95% Miettinen-Nurminen confidence interval (CI).” (opens the prescribing information at this quote)
“Based on two-sided p-value (Boschloo's test).” (opens the prescribing information at this quote)

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

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.” (opens the prescribing information at this quote)

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).” (opens the prescribing information at this quote)
“Overall: results are based on pooled data; Rate Difference: common rate difference (Miettinen-Nurminen method)” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)

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).” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)
“In the FAS of 856 participants who received at least one dose of HIBSAGO or placebo” (opens the prescribing information at this quote)

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” (opens the prescribing information at this quote)

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” (opens the prescribing information at this quote)

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” (opens the prescribing information at this quote)

Baseline ALT and HBeAg status

“93% had ALT ≤ULN at baseline; 92% were HBeAg negative at baseline” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)

Balance between treatment groups

“In each trial, demographic characteristics were generally balanced between HIBSAGO and placebo participants.” (opens the prescribing information at this quote)

Primary and key secondary endpoints met

“Within both trials, the primary and key secondary endpoints were met.” (opens the prescribing information at this quote)

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”

“and in the B-Well 2 trial (in 106 of 570 patients [19%] vs. none of 286 patients)” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

Key secondary endpoint: sustained HBV DNA suppression and HBsAg not detected, baseline HBsAg up to 1,000 IU/mL

Measure (full analysis set)	Value
Hibsago, n/N (%)	“95/342 (28)”
Placebo, n/N (%)	“0/179 (0)”
Rate difference, % (95% CI)	“28 (23.3, 32.8)”
p-value	“<0.0001”

Key secondary endpoints: sustained HBV DNA suppression below the LLOQ 24 weeks after NrtI cessation

Measure (full analysis set)	Value
Baseline HBsAg up to 3,000 IU/mL: Hibsago, n/N (%)	“132/570 (23)”
Baseline HBsAg up to 3,000 IU/mL: placebo, n/N (%)	“0/286 (0)”
Baseline HBsAg up to 3,000 IU/mL: common rate difference, % (95% CI)	“18 (15.1, 21.3)”
Baseline HBsAg up to 1,000 IU/mL: Hibsago, n/N (%)	“113/342 (33)”
Baseline HBsAg up to 1,000 IU/mL: placebo, n/N (%)	“0/179 (0)”
Baseline HBsAg up to 1,000 IU/mL: rate difference, % (95% CI)	“33 (28.3, 38.2)”
p-value, each stratum	“<0.0001”

Functional cure at week 72 by baseline HBsAg stratum, pooled and B-Well 2

Population	Value
Pooled, baseline HBsAg up to 3,000 IU/mL: rate	“19% vs. 0% (placebo)”
Pooled, baseline HBsAg up to 3,000 IU/mL: participants	“233 of 1,220 vs. 0 of 614”
B-Well 2, baseline HBsAg up to 3,000 IU/mL: rate	“B-Well 2: 19% vs. 0%”
B-Well 2, baseline HBsAg up to 3,000 IU/mL: participants	“106 of 570 vs. 0 of 286”
Pooled, baseline HBsAg up to 1,000 IU/mL: rate	“26% vs. 0% (placebo)”
Pooled, baseline HBsAg up to 1,000 IU/mL: participants	“200 of 768 vs. 0 of 393”
B-Well 2, baseline HBsAg up to 1,000 IU/mL: rate	“B-Well 2: 28% vs. 0%”
B-Well 2, baseline HBsAg up to 1,000 IU/mL: participants	“95 of 342 vs. 0 of 179”

Nucleotide polymorphisms in the bepirovirsen binding site

Population and measure	Value
Baseline HBsAg up to 3,000 IU/mL: baseline polymorphisms, % (n/N)	“7 (7/104)”
Baseline HBsAg up to 3,000 IU/mL: treatment-emergent mutations, % (n/N)	“6 (2/31)”
Baseline HBsAg up to 1,000 IU/mL: baseline polymorphisms, % (n/N)	“12 (6/50)”
Baseline HBsAg up to 1,000 IU/mL: treatment-emergent mutations, % (n/N)	“0 (0/10)”

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)” (opens the prescribing information at this quote)

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

Summary: study limitations

B-Well 2 had the same design as B-Well 1: bepirovirsen was administered for 24 weeks, the primary endpoint was assessed at week 72, 24 weeks after possible cessation of NrtI therapy, and the longest reported follow-up is week 96, covering the 295 of 1,220 pooled bepirovirsen recipients who stopped NrtI therapy at week 48. Eligibility required stable NrtI therapy, HBsAg above 100 and up to 3,000 IU/mL, HBV DNA below 90 IU/mL, and ALT up to 2 times the upper limit of normal, and excluded participants with cirrhosis, HCV, HIV, or HDV coinfection, eGFR at or below 60 mL/min/1.73 m2, or platelet count below 140 × 10⁹/L. Participants were randomized to bepirovirsen or placebo added to background NrtI therapy, with no active-comparator group. In the full analysis set, 92% of participants were HBeAg negative, 6% were enrolled in the US and Canada, and 2% had an unknown genotype. The label reports safety data for B-Well 1 and B-Well 2 only as pooled results, and neither the label nor the published abstract reports health-related quality of life or patient-reported outcome results.

Small number of participants aged 75 years and older

“Differences in efficacy in this age group versus younger adult patients cannot be determined due to the small number of participants.” (opens the prescribing information at this quote)

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” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)
“There are no data on the effect of HIBSAGO in preventing transmission of HBV.” (opens the prescribing information at this quote)

Unknown clinical impact of binding-site variants with reduced susceptibility

“The clinical impact of reduced susceptibility to HIBSAGO in these variants is unknown.” (opens the prescribing information at this quote)