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 in HBV DNA suppression off-treatment after a finite duration of therapy in participants with chronic HBV infection on NA treatment” (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” (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) 2022-12-07” (opens the source at this quote in a new tab)
“Primary Completion (Actual) 2025-11-11” (opens the source at this quote in a new tab)
“Study Completion (Actual) 2026-04-15” (opens the source at this quote in a new tab)
“First Posted 2022-11-30” (opens the source at this quote in a new tab)
“Last Update Posted 2026-07-08” (opens the source at this quote in a new tab)
“Completed” (opens the source at this quote in a new tab)
“No Results Posted” (opens the source at this quote in a new tab)

Number of locations in the ClinicalTrials.gov record

“This study has 177 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	“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”

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” (opens the source at this quote in a new tab)
“Start of trial 09/01/2023” (opens the source at this quote in a new tab)
“End of trial 17/03/2026” (opens the source at this quote in a new tab)
“Global end of trial 15/04/2026” (opens the source at this quote in a new tab)
“Estimated recruitment start date in EU/EEA: 13/01/2023” (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 2023-01-26” (opens the source at this quote in a new tab)
“Date of Ethics Committee Opinion 2022-12-16” (opens the source at this quote in a new tab)

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” (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 1)” (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) 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).” (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)
“<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)
“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) 981” (opens the source at this quote in a new tab)

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

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.” (opens the prescribing information at this quote)
“In the full analysis set (FAS) of 978 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)	“127/650”	“0/328”
Baseline HBsAg up to 1,000 IU/mL (first key secondary endpoint)	“105/426”	“0/214”

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)” (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 full analysis set (FAS) of 978 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 1, a total of 981 participants were randomized (2:1) to receive either HIBSAGO or placebo.” (opens the prescribing information at this quote)
“In the full analysis set (FAS) of 978 participants who received at least one dose of HIBSAGO or placebo” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)

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” (opens the prescribing information at this quote)

“Across the two trials, 24% of patients who received Hibsago met the requirements to stop their existing medicine, compared with none who received placebo.” (opens the source at this quote in a new tab)

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” (opens the prescribing information at this quote)

Geographic region of enrollment

“58% were in Asia, 25% were in Europe, 10% were in Latin America, and 7% were in US and Canada” (opens the prescribing information at this quote)

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” (opens the prescribing information at this quote)

Baseline ALT and HBeAg status

“91% had ALT ≤ULN at baseline; 92% were HBeAg negative at baseline” (opens the prescribing information at this quote)

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.” (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)

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.” (opens the prescribing information at this quote)
“In the B-Well 1 and B-Well 2 trials, 21 (1%) participants were 75 years of age and older.” (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 (%)	“127/650 (20)”
Placebo, n/N (%)	“0/328 (0)”
Common rate difference, % (95% CI)	“17 (14.6, 20.3)”
p-value	“<0.0001”

“The percentage of patients with a functional cure at week 72 was significantly higher with bepirovirsen than with placebo both in the B-Well 1 trial (in 127 of 650 patients [20%] vs. none of 328 patients)” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

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

Measure (full analysis set)	Value
Hibsago, n/N (%)	“105/426 (25)”
Placebo, n/N (%)	“0/214 (0)”
Rate difference, % (95% CI)	“25 (20.8, 29.0)”
p-value	“<0.0001”

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

Measure (full analysis set)	Value
Baseline HBsAg up to 3,000 IU/mL: Hibsago, n/N (%)	“151/650 (23)”
Baseline HBsAg up to 3,000 IU/mL: placebo, n/N (%)	“0/328 (0)”
Baseline HBsAg up to 3,000 IU/mL: common rate difference, % (95% CI)	“21 (17.9, 24.0)”
Baseline HBsAg up to 1,000 IU/mL: Hibsago, n/N (%)	“124/426 (29)”
Baseline HBsAg up to 1,000 IU/mL: placebo, n/N (%)	“0/214 (0)”
Baseline HBsAg up to 1,000 IU/mL: rate difference, % (95% CI)	“29 (25.0, 33.6)”
p-value, each stratum	“<0.0001”

Functional cure at week 72 by baseline HBsAg stratum, pooled and B-Well 1

Population	Value
Pooled, baseline HBsAg up to 3,000 IU/mL: rate	“19% vs. 0% (placebo)”
Pooled, baseline HBsAg up to 3,000 IU/mL: participants	“233 of 1,220 vs. 0 of 614”
B-Well 1, baseline HBsAg up to 3,000 IU/mL: rate	“B-Well 1: 20% vs. 0%”
B-Well 1, baseline HBsAg up to 3,000 IU/mL: participants	“127 of 650 vs. 0 of 328”
Pooled, baseline HBsAg up to 1,000 IU/mL: rate	“26% vs. 0% (placebo)”
Pooled, baseline HBsAg up to 1,000 IU/mL: participants	“200 of 768 vs. 0 of 393”
B-Well 1, baseline HBsAg up to 1,000 IU/mL: rate	“B-Well 1: 25% vs. 0%”
B-Well 1, baseline HBsAg up to 1,000 IU/mL: participants	“105 of 426 vs. 0 of 214”

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

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

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” (opens the source at this quote in a new tab)
“as of the week 72 visit.” (opens the source at this quote in a new tab)

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).” (opens the prescribing information at this quote)
“The efficacy response was generally higher for age <65 versus that for age ≥65 years” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)
“Overall response rates were 28% for genotype A, 21% for genotype B, 20% for genotype D, and 15% for genotype C.” (opens the prescribing information at this quote)
“Response rates declined with increasing baseline HBsAg levels and fell below 10% for genotypes B and C at baseline HBsAg levels exceeding 1,000 IU/mL.” (opens the prescribing information at this quote)

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

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.” (opens the prescribing information at this quote)
“Of the 233 participants who met the primary endpoint at Week 72, 91% (211/233) maintained response off all HBV treatment at Week 96.” (opens the prescribing information at this quote)

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

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)”

Pooled B-Well 1 and B-Well 2 results: overall, serious, and grade 3 or higher adverse events

“In a pooled analysis at 72 weeks, adverse events were reported in 91% of the patients in the bepirovirsen groups and in 73% of those in the placebo groups; serious adverse events were reported in 7% and 4% of the patients, respectively.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“During the treatment period, adverse events of grade 3 or higher were reported in 16% of the patients who received bepirovirsen and in 3% of those who received placebo; increases in the alanine aminotransferase level were the most common grade 3 adverse events with bepirovirsen (in 6% of the patients).” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

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

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

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%”

“Fatigue includes the preferred terms asthenia, fatigue, malaise, lethargy and sluggishness.” (opens the prescribing information at this quote)

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%”

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

Pooled B-Well 1 and B-Well 2 results: selected laboratory abnormalities worsened from baseline, weeks 1 to 36

Laboratory category	Hibsago (N = 1,223)	Placebo (N = 611)
ALT 3 to less than 5 times ULN	“10%”	“<1%”
ALT 5 to less than 10 times ULN	“8%”	“0”
ALT 10 to less than 20 times ULN	“4%”	“0”
ALT 20 times ULN or higher	“2%”	“<1%”
AST 3 to less than 5 times ULN	“6%”	“<1%”
AST 5 to less than 10 times ULN	“4%”	“<1%”
AST 10 to less than 20 times ULN	“1%”	“<1%”
AST 20 times ULN or higher	“<1%”	“0”
Total bilirubin ULN to less than 1.5 times ULN	“8%”	“11%”
Total bilirubin 1.5 to less than 2 times ULN	“2%”	“2%”
Total bilirubin 2 times ULN or higher	“<1%”	“<1%”
Platelets 100 to less than 140 x 10^9/L	“37%”	“7%”
Platelets 75 to less than 100 x 10^9/L	“8%”	“<1%”
Platelets 50 to less than 75 x 10^9/L	“2%”	“<1%”
Platelets 25 to less than 50 x 10^9/L	“<1%”	“0”
Platelets less than 25 x 10^9/L	“<1%”	“0”
ANC 500 to less than 1,000 cells/mm3	“8%”	“3%”
ANC 100 to less than 500 cells/mm3	“1%”	“<1%”
eGFR decline of 15% to less than 30% from baseline	“51%”	“30%”
eGFR decline of 30% to less than 50% from baseline	“17%”	“6%”
eGFR decline of 50% or more from baseline	“1%”	“<1%”
uACR 0.3 mg/mg or higher	“2%”	“1%”

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

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

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.” (opens the prescribing information at this quote)
“This participant was assessed as having immune thrombocytopenia. Both participants recovered with corticosteroid treatment and permanent discontinuation of HIBSAGO” (opens the prescribing information at this quote)
“In total, 8 (<1%) participants met permanent discontinuation criteria, and 114 (9%) participants paused treatment due to platelet declines.” (opens the prescribing information at this quote)
“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.” (opens the prescribing information at this quote)
“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).” (opens the prescribing information at this quote)

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.” (opens the prescribing information at this quote)
“The decline in neutrophil count was not associated with adverse events that indicated increased risk of infection.” (opens the prescribing information at this quote)

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” (opens the prescribing information at this quote)
“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.” (opens the prescribing information at this quote)
“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.” (opens the prescribing information at this quote)
“The mean eGFR in the HIBSAGO group recovered to within 5% of baseline values by Week 36 (12 weeks after last dose of HIBSAGO).” (opens the prescribing information at this quote)

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

“Adverse reactions of biopsy-confirmed vasculitis occurred in two participants treated with HIBSAGO.” (opens the prescribing information at this quote)
“leukocytoclastic vasculitis, and the events resolved with corticosteroid treatment after permanent discontinuation of HIBSAGO” (opens the prescribing information at this quote)

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:” (opens the prescribing information at this quote)
“Immune system disorders: Hypersensitivity” (opens the prescribing information at this quote)
“Skin and soft tissue disorders: Angioedema” (opens the prescribing information at this quote)

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

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.” (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 1 administered bepirovirsen for 24 weeks and assessed the primary endpoint at week 72, 24 weeks after possible cessation of NrtI therapy; the longest reported follow-up is week 96, and it covers the 295 of 1,220 pooled bepirovirsen recipients who stopped NrtI therapy at week 48. Eligibility required stable NrtI therapy, HBsAg above 100 and up to 3,000 IU/mL, HBV DNA below 90 IU/mL, and ALT up to 2 times the upper limit of normal, and excluded participants with cirrhosis, HCV, HIV, or HDV coinfection, eGFR at or below 60 mL/min/1.73 m2, or platelet count below 140 × 10⁹/L. Participants were randomized to bepirovirsen or placebo added to background NrtI therapy, with no active-comparator group. In the full analysis set, 92% of participants were HBeAg negative and 7% were enrolled in the US and Canada, and the label states that efficacy differences in participants aged 75 years and older “cannot be determined due to the small number of participants”. The label reports safety data for B-Well 1 and B-Well 2 only as pooled results, and neither the label nor the published abstract reports health-related quality of life or patient-reported outcome results.

Small number of participants aged 75 years and older

“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)