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Hibsago (bepirovirsen)

Chronic hepatitis B virus infection in adults without cirrhosis

Also known as GSK3228836
Manufacturer
GSK
Last updated
190 sources

New drug review

Hibsago

Review section

FieldValue
DrugHibsago (bepirovirsen)
Indication reviewedIn combination with nucleos(t)ide analog reverse transcriptase inhibitor (NrtI) therapy, treatment of chronic hepatitis B virus (HBV) infection in adults without cirrhosis who have been on NrtI therapy for at least 6 months, have suppressed HBV DNA, and have HBV surface antigen (HBsAg) levels of 3,000 IU/mL or less as determined by an FDA-authorized test
Therapeutic categoryHepatitis B virus messenger RNA-directed antisense oligonucleotides
ManufacturerGSK (GlaxoSmithKline)
Regulatory statusApproved October 20, 2026
Data as ofOctober 21, 2026
Review statusDraft for pharmacy and therapeutics committee review

Indications

Table 1. FDA-approved indications

IndicationsHibsago (bepirovirsen)
“HIBSAGO is indicated in combination with nucleos(t)ide analog reverse transcriptase inhibitor (NrtI) therapy for treatment of chronic hepatitis B virus (HBV) infection in adult patients without cirrhosis:”“who have been on NrtI therapy for at least 6 months and have suppressed HBV deoxyribonucleic acid (DNA), and”“who have HBV surface antigen (HBsAg) levels less than or equal to 3,000 IU/mL as determined by an FDA-authorized test”✓

Pharmacologic class and required combination with nucleos(t)ide analog therapy

“HIBSAGO is a hepatitis B virus (HBV) mRNA-directed antisense oligonucleotide (ASO) indicated in combination with nucleos(t)ide analog reverse transcriptase inhibitor (NrtI) therapy for treatment of chronic HBV infection in adult patients without cirrhosis:” (opens the prescribing information at this quote)

“HIBSAGO is administered by subcutaneous injection and must be used in combination with NrtI therapy.” (opens the prescribing information at this quote)

Baseline HBsAg testing required for patient selection

“Prior to initiation of HIBSAGO for treatment of chronic HBV infection, test all patients to quantify HBsAg levels in serum or plasma to identify patients with baseline HBsAg levels less than or equal to 3,000 IU/mL” (opens the prescribing information at this quote)

“In addition, test patients for HBV DNA, ALT, AST, bilirubin, platelet count, urine albumin-creatinine ratio (uACR), and estimated glomerular filtration rate (eGFR) prior to initiation of treatment and as directed while on treatment and following treatment completion” (opens the prescribing information at this quote)

“Information on FDA-authorized tests for the quantification of HBsAg levels is available at:” (opens the prescribing information at this quote)

Populations excluded from or not studied under the indication

“Patients with acute hepatic impairment, or cirrhosis who have mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B or C)” (opens the prescribing information at this quote)

“Patients with platelet count below 100 x 109/L prior to initiation of treatment” (opens the prescribing information at this quote)

“HIBSAGO is not recommended in patients with Hepatitis D Virus (HDV) coinfection due to the potential for an exacerbated risk of clinically significant ALT increases.” (opens the prescribing information at this quote)

“The safety and efficacy of HIBSAGO have not been established in patients with hepatitis C virus (HCV) coinfection.” (opens the prescribing information at this quote)

Age range of the indication

“The safety and effectiveness of HIBSAGO have not been established in patients less than 18 years of age.” (opens the prescribing information at this quote)

“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. The efficacy response was generally higher for age <65 versus that for age ≥65 years [see Clinical Studies (14)]. 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)

“In the B-Well 1 and B-Well 2 trials, 21 (1%) participants were 75 years of age 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)

Pharmacokinetics

Table 2. Pharmacokinetic parameters

Generic Name(s)BioavailabilityProtein BindingMetabolismExcretionHalf-Life
BepirovirsenNot reportedPlasma protein binding: “99% at 5 mcg/mL”“95% at 150 mcg/mL”Primary pathway: “Metabolized in tissues by endonucleases to form shorter oligonucleotides that are then substrates for additional metabolism by exonucleases”Major route of elimination: “Metabolism”Urine: “Oligonucleotide fragments are expected to be excreted by the kidney”Terminal half-life (days), observed median (min-max): “29 (8-192)”

How the label reports pharmacokinetic values

“The pharmacokinetic parameters of bepirovirsen 300 mg are summarized in Table 7.” (opens the prescribing information at this quote)

“Pharmacokinetic parameters are presented as arithmetic mean (SD), derived from population PK model simulations at steady state following subcutaneous administration of HIBSAGO 300 mg weekly in participants with chronic HBV infection (CHB).” (opens the prescribing information at this quote)

“observed median (min-max)” (opens the prescribing information at this quote)

“Pharmacokinetic parameters are presented as geometric mean (CV%) from post-hoc individual estimates from Phase 3 population PK model.” (opens the prescribing information at this quote)

Exposure, absorption, distribution, and clearance at 300 mg weekly

ParameterPrescribing information
Cmax (mcg/mL), arithmetic mean (SD)“9.14 (2.19)”
AUC0-tau (mcg*hour/mL), arithmetic mean (SD)“102 (34.3)”
Ctrough (mcg/mL), arithmetic mean (SD)“0.022 (0.045)”
Dose proportionality“Exposure increased in proportion to dose over the range of 150 to 300 mg weekly dosing”
Time to steady state“Steady state concentration is reached by Day 8 following 300 mg weekly dosing with loading doses during Weeks 1 and 2”
Accumulation“No accumulation was observed with 300 mg weekly dosing for 24 weeks”
Tmax (hours), observed median (min-max)“3 (2-5)”
Vss/F (L), geometric mean (CV%)“73 (46.3)”
Clearance/F (L/hour), geometric mean (CV%)“3.05 (25.7)”

Specific populations

“Based on population pharmacokinetic analyses, following subcutaneous administration, there were no clinically meaningful changes in the pharmacokinetics of bepirovirsen by race (Asian, Black, White, Other), ethnicity,” (opens the prescribing information at this quote)

“age (18-87 years old), sex, body weight (39 kg to 148 kg), injection site location (thigh, upper arm, abdomen) and anti-drug antibodies (ADA) status.” (opens the prescribing information at this quote)

“Renal Impairment: Bepirovirsen pharmacokinetics were similar between patients with CHB with an eGFR 60 to 89 mL/min/1.73m2 compared to patients with an eGFR ≥90 mL/min/1.73 m2. Insufficient data are available in patients with moderate or severe renal impairment.” (opens the prescribing information at this quote)

“Hepatic Impairment: The pharmacokinetics of bepirovirsen have not been evaluated in CHB patients with hepatic impairment (Child-Pugh Class A, B, or C) [see Contraindications (4)].” (opens the prescribing information at this quote)

“There is a 33% reduction in Cmax and a 31% reduction in AUC0-∞ in participants with moderate hepatic impairment (Child-Pugh Class B) but without HBV infection when compared to participants with normal hepatic function.” (opens the prescribing information at this quote)

Immunogenicity and clearance

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

Mechanism of action and antiviral activity

“HIBSAGO (bepirovirsen) injection is a hepatitis B virus (HBV) messenger RNA-directed antisense oligonucleotide.” (opens the prescribing information at this quote)

“HIBSAGO is an antiviral drug against HBV [see Microbiology (12.4)].” (opens the prescribing information at this quote)

“Bepirovirsen is a synthetic, single-stranded, chimeric antisense oligonucleotide (ASO) with a gapmer architecture consisting of five 2′-O-(2-methoxyethyl) (2′-MOE)-modified ribonucleotide wings flanking a central 10-deoxynucleotide gap with phosphorothioate linkages throughout.” (opens the prescribing information at this quote)

“Bepirovirsen is designed to bind a conserved 20-nucleotide site” (opens the prescribing information at this quote)

“present in HBV mRNAs (including the pregenomic RNA [pgRNA], precore, preS1, preS2/S, and X mRNAs), forming a DNA:RNA heteroduplex that recruits endogenous ribonuclease H1 (RNase H1) to catalyze irreversible hydrolysis of the viral RNA strand at the 3’-O-P bonds, resulting in degradation of HBV mRNA and reduction in HBV DNA and viral proteins, including HBsAg.” (opens the prescribing information at this quote)

“The 20-nucleotide binding site is present within transcripts derived from both cccDNA and integrated HBV DNA.” (opens the prescribing information at this quote)

“Conservation of the bepirovirsen target site across HBV genotypes indicates broad antiviral activity.” (opens the prescribing information at this quote)

“Bioinformatic analysis of 9,139 HBV genomes in the HBV database showed that the target sequence is conserved across genotypes A-H and recombinant forms, with full identity to 97.6% of sequences, and to 99.7% of sequences when allowing for one nucleotide mismatch.” (opens the prescribing information at this quote)

Immunostimulant activity

“In nonclinical studies, bepirovirsen exhibited innate immune activity in a sequence-specific, human toll-like receptor 8 (hTLR8)-dependent manner, with no activity observed at other pattern recognition receptors tested.” (opens the prescribing information at this quote)

“In clinical studies, administration of HIBSAGO was associated with increases in innate immune markers of activation and trafficking, which included cytokines and chemokines (e.g., interleukin12, tumor necrosis factor, interferon gamma and CXC motif chemokine ligand 9 and 10). Treatment with HIBSAGO also increased total IgM.” (opens the prescribing information at this quote)

“The contribution of immunostimulatory activity to antiviral activity at therapeutic concentrations in humans has not been fully determined.” (opens the prescribing information at this quote)

Exposure-response and cardiac electrophysiology

“Within the range of bepirovirsen exposures achieved at the dosing regimen in B-Well 1 and B-Well 2 trials, variability in bepirovirsen plasma exposure was not identified as a determinant of treatment response at Week 72.” (opens the prescribing information at this quote)

“At supratherapeutic doses of 450 or 600 mg (1.5 and 2 times the recommended dosage) of HIBSAGO, clinically significant QTc interval prolongation was not observed.” (opens the prescribing information at this quote)

Drug interactions

Table 3. Major drug interactions

Generic Name(s)InteractionMechanism
BepirovirsenAnticoagulants, antiplatelets, and drugs that decrease platelet count“Monitor patients for signs of bleeding and thrombocytopenia if HIBSAGO is taken concomitantly with anticoagulants, antiplatelets, or drugs that decrease platelet count”“HIBSAGO may cause reductions in platelet count at any time during treatment that may result in sudden and unpredictable thrombocytopenia that can be life-threatening.”“a gradual, dose-dependent decline in platelet count was observed in most patients that continued to worsen while on HIBSAGO.”“Consider the risks and benefits of treatment with HIBSAGO when treating patients who may be particularly susceptible to platelet count decreases, e.g., elderly patients, or patients with bleeding diathesis/coagulopathy, history of major bleeding events or patients taking antiplatelets, anticoagulants, or drugs that lower platelet count”
BepirovirsenDrugs that impair renal function“Monitor patients for signs of worsening renal function during concomitant administration of HIBSAGO with drugs that may impair renal function. Refer to individual drug information before prescribing”“In the HIBSAGO clinical trials, mean eGFR declined within 4 weeks of initiation of HIBSAGO and continued to decline during treatment.”“Consider the risks and benefits of HIBSAGO when treating patients who may be more susceptible to renal injury”
BepirovirsenPeginterferon alfa-2a“Concomitant administration of HIBSAGO and peginterferon alfa-2a is not recommended due to the potential for an exacerbated risk of increased ALT, decreased platelet count, and immune-mediated effects.”
BepirovirsenNucleos(t)ide analog reverse transcriptase inhibitors“No formal clinical drug interaction studies have been conducted with HIBSAGO. In clinical trials, concomitant administration of HIBSAGO with a NrtI did not result in changes in bepirovirsen exposure.”“In addition, HIBSAGO did not impact NrtI exposure.”“HIBSAGO must be used in combination with NrtI therapy. Refer to the NrtI prescribing information for additional information.”
BepirovirsenCytochrome P450 enzymes and drug transporters (in vitro)“Based on in vitro study results, HIBSAGO is not a substrate, inducer or inhibitor of major cytochrome P450 (CYP) enzymes, or drug transporters; therefore, clinically relevant pharmacokinetic interactions are not expected.”

Abbreviations: ALT=alanine aminotransferase; CYP=cytochrome P450; eGFR=estimated glomerular filtration rate; NrtI=nucleos(t)ide analog reverse transcriptase inhibitor

Antiviral activity in combination with entecavir or tenofovir and cross-resistance

“Combining bepirovirsen with entecavir or tenofovir disoproxil fumarate in HepG2.2.15 cells (HBV genotype D, transfection-based delivery) resulted in no antagonism and greater reductions of intracellular HBV DNA by qPCR compared to the individual drugs.” (opens the prescribing information at this quote)

“Cross-resistance between bepirovirsen and NrtIs including entecavir and tenofovir is not expected. The bepirovirsen target site (encoding polymerase amino acid residues 832–839) is located in a region distinct from the reverse transcriptase domain associated with NrtI resistance substitutions (polymerase amino acid residues 385–605). The bepirovirsen target site does not overlap with HBV vaccine epitope coding sequences.” (opens the prescribing information at this quote)

Nucleos(t)ide analog therapy in HIV-1 and HBV coinfection

“Patients who are taking nucleos(t)ide analog reverse transcriptase inhibitors as part of antiretroviral therapy for HIV-1 and HBV coinfection must not stop taking their nucleos(t)ide analog reverse transcriptase inhibitor therapy unless an HIV healthcare provider has directed them to do so.” (opens the prescribing information at this quote)

“Advise patients living with HIV who are taking NrtI therapy for both HIV and HBV to not discontinue NrtI therapy except under the direct supervision of an HIV healthcare provider” (opens the prescribing information at this quote)

Drug-disease interaction: hepatitis D virus coinfection

“There are no data on the safety and efficacy of HIBSAGO in patients with HBV and hepatitis D virus (HDV) coinfection. HIBSAGO is not recommended in patients with HDV coinfection due to the potential for an exacerbated risk of clinically significant ALT increases.” (opens the prescribing information at this quote)

Medicines the Medication Guide asks patients to report

“Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.” (opens the prescribing information at this quote)

“Using HIBSAGO with certain other medicines may increase the risk of side effects.” (opens the prescribing information at this quote)

“medicines that prevent your blood from clotting or that lower your blood platelet count.” (opens the prescribing information at this quote)

“medicines that may lower your kidney function.” (opens the prescribing information at this quote)

“peginterferon alfa-2a.” (opens the prescribing information at this quote)

Adverse drug events

Table 4. Adverse drug events reported in 3% or more of Hibsago recipients, and at a frequency at least 2% greater than placebo, in B-Well 1 and B-Well 2 through week 36

Adverse EventHibsago (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%”

Adverse reactions as the label states them

“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)

“The most common adverse reactions (≥10%), excluding laboratory abnormalities, reported with HIBSAGO included injection site reactions, pyrexia, fatigue, and headache.” (opens the prescribing information at this quote)

“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)

“Frequencies of adverse reactions are based on all adverse events, regardless of investigator assessment of causality, excluding laboratory abnormalities reported as adverse events” (opens the prescribing information at this quote)

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

“Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.” (opens the prescribing information at this quote)

Less common adverse reactions

“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)

Injection site reactions reported in 3% or more of Hibsago recipients in B-Well 1 and B-Well 2 through week 36

Injection site reaction (all grades)Hibsago (N = 1,223), %Placebo (N = 611), %
Any injection site reaction“57%”“15%”
Injection site erythema“32%”“2%”
Injection site pain“24%”“6%”
Injection site pruritus“19%”“1%”
Injection site bruising“19%”“6%”
Injection site induration/swelling“13%”“1%”
Injection site discoloration“8%”“<1%”
Injection site rash“6%”“<1%”
Injection site hematoma“4%”“1%”

Injection site reactions as the label states them

“ISRs were the most common adverse reactions reported with HIBSAGO.” (opens the prescribing information at this quote)

“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)

“Frequencies of injection site reactions are based on all adverse events, regardless of investigator assessment of causality.” (opens the prescribing information at this quote)

“To provide accurate frequencies, pooled injection site reaction categories were constructed to combine adverse event preferred terms describing the same type of injection site reaction.” (opens the prescribing information at this quote)

“Individual participants may have reported more than one type of injection site reaction.” (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)

Selected laboratory abnormalities worsened from baseline in B-Well 1 and B-Well 2 through week 36

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

How the label counts laboratory abnormalities

“Each participant is only counted once per parameter with the laboratory value that represents their largest change from baseline in Weeks 1-36.” (opens the prescribing information at this quote)

“Information based on laboratory values reported from the central laboratory for B-Well 1 and B-Well 2 (local laboratory results were not included).” (opens the prescribing information at this quote)

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)

Platelet count decreases

“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. 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)

Neutrophil count decreases

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

“In the pivotal clinical trials, the maximum change from baseline in absolute neutrophil count in the HIBSAGO group occurred at Week 24, with a mean (SD) change from baseline of -0.795 x 109/L (1.0969) or -20.36% (29.40), from a baseline of 3.33 x 109/L.” (opens the prescribing information at this quote)

“The mean absolute neutrophil 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)

eGFR decreases

“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. 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)

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)

Adverse events, serious adverse events, and grade 3 or higher adverse events in the trial publication, which the prescribing information does not report

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

Boxed warning: on-treatment hepatic flares and thrombocytopenia

“HIBSAGO may cause on-treatment hepatic flares with increases in ALT of >20-40x ULN associated with decline in HBsAg. Some cases were associated with hyperbilirubinemia. Most occurred in the first 12 weeks of treatment and resolved when treatment was interrupted or permanently discontinued” (opens the prescribing information at this quote)

“ALT and total bilirubin must be measured prior to initiation of HIBSAGO and frequently monitored during treatment” (opens the prescribing information at this quote)

“Interruption of treatment, followed by reducing the dose or discontinuation of HIBSAGO, may be necessary based on the results of liver laboratory tests” (opens the prescribing information at this quote)

“HIBSAGO may cause reductions in platelet counts that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening.” (opens the prescribing information at this quote)

“Prior to starting HIBSAGO, obtain a platelet count to ensure the patient is eligible for treatment” (opens the prescribing information at this quote)

“During treatment, monitor platelet counts weekly if values are 75 x 109/L or greater, and more frequently if values are less than 75 x 109/L” (opens the prescribing information at this quote)

“If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible. The patient should not receive additional doses of HIBSAGO unless platelet counts return to 100 x 109/L or greater. If platelet count falls below 50 x 109/L, treatment with HIBSAGO should be permanently discontinued” (opens the prescribing information at this quote)

Contraindications

“HIBSAGO is contraindicated in patients:” (opens the prescribing information at this quote)

“with acute hepatic impairment, or cirrhosis who have mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C)” (opens the prescribing information at this quote)

“with a platelet count below 100 x 109/L prior to initiation of treatment” (opens the prescribing information at this quote)

Warning: on-treatment hepatic flares

“During treatment with HIBSAGO, increases in ALT ≥3 x ULN to 69 x ULN were observed in clinical trials” (opens the prescribing information at this quote)

“Most ALT increases occurred in the first 12 weeks of treatment (typically between Weeks 5 to 10), started to resolve within 2 weeks, and were not associated with any clinical signs or symptoms of liver dysfunction. The ALT increases were temporally associated with a preceding or concurrent decline in HBsAg suggesting host immune response. Two percent of participants receiving HIBSAGO had ALT increases ≥20 x ULN that resolved when treatment was interrupted or permanently discontinued.” (opens the prescribing information at this quote)

“isolated cases of ALT increases associated with an increase in total bilirubin up to 4 x ULN that resolved when treatment was permanently discontinued.” (opens the prescribing information at this quote)

Warning: thrombocytopenia

“HIBSAGO may cause reductions in platelet count at any time during treatment that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In the HIBSAGO clinical trials, two participants reported serious adverse reactions of thrombocytopenia <50 × 10⁹/L, including one participant with immune thrombocytopenia” (opens the prescribing information at this quote)

“In patients with platelet count below the normal range but ≥100 x 109/L, rule out cirrhosis before initiating HIBSAGO” (opens the prescribing information at this quote)

“If platelet count falls below 50 x 109/L, permanently discontinue treatment with HIBSAGO and consider corticosteroid treatment in consultation with an expert.” (opens the prescribing information at this quote)

“Symptoms of thrombocytopenia can include unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache.” (opens the prescribing information at this quote)

Warning: worsening renal function

“In the HIBSAGO clinical trials, mean eGFR declined within 4 weeks of initiation of HIBSAGO and continued to decline during treatment. These changes were generally reversible after treatment discontinuation. The mechanism of the decrease in eGFR is not clear” (opens the prescribing information at this quote)

“Obtain eGFR and uACR in all patients prior to initiation of treatment.” (opens the prescribing information at this quote)

“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)

“Although no cases of glomerulonephritis were observed with HIBSAGO administration in the clinical trials, glomerulonephritis has been observed after administration of other antisense oligonucleotides. Consider assessing for proteinuria periodically during treatment, as appropriate. If a diagnosis of glomerulonephritis is suspected or confirmed, permanently discontinue HIBSAGO and consider early initiation of immunosuppressive therapy in consultation with an expert.” (opens the prescribing information at this quote)

Warning: inflammatory and immune effects

“In trials with HIBSAGO, influenza-like symptoms, laboratory test changes (e.g., decreases in complement factors C3 and C4), purpuric leg rashes, cutaneous leukocytoclastic vasculitis, dermatitis, pruritus/erythematous plaque, and polyarthralgia were observed. In addition, serious inflammatory and immune adverse reactions were reported, including immune thrombocytopenia, autoimmune hemolytic anemia, systemic inflammatory response syndrome, and a cryoglobulinemic flare” (opens the prescribing information at this quote)

“Consider the risks and benefits of HIBSAGO when treating patients that may be more susceptible to inflammatory and/or immune effects, e.g., solid organ transplant recipients, patients with autoimmune hepatitis, or patients with a history of vasculitis or conditions associated with vasculitis (including systemic lupus erythematosus, cryoglobulinemia, or rheumatoid arthritis).” (opens the prescribing information at this quote)

“If signs and symptoms suggestive of vasculitis/immune-associated events occur, and no alternative cause is identified, permanently discontinue treatment with HIBSAGO.” (opens the prescribing information at this quote)

Warning: serious adverse reaction with improper administration

“Improper HIBSAGO administration, including not rotating injection sites, has been associated with the serious adverse reaction of omental infarction in one participant.” (opens the prescribing information at this quote)

“Ensure that injection sites are rotated from one week to the next and that the two injections administered weekly to constitute the recommended dose of HIBSAGO are separated by at least 2 inches (5 cm).” (opens the prescribing information at this quote)

Warnings: exacerbations after nucleos(t)ide analog discontinuation and transmission of HBV

“Severe acute exacerbations of HBV infection may occur after discontinuation of anti-HBV therapy. If NrtI therapy is discontinued after completing HIBSAGO treatment, frequent monitoring is recommended.” (opens the prescribing information at this quote)

“There are no data on the effect of HIBSAGO in preventing transmission of HBV. Patients must be advised to use appropriate precautions to prevent transmission of HBV.” (opens the prescribing information at this quote)

Pregnancy and lactation

“There are insufficient data on the use of HIBSAGO in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental or reproductive effects were observed when bepirovirsen was administered subcutaneously to mice and rabbits at less than 1 (mouse) and approximately 3 (rabbits) times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparisons (see Data).” (opens the prescribing information at this quote)

“The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.” (opens the prescribing information at this quote)

“In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.” (opens the prescribing information at this quote)

“Reduced fetal weights associated with maternal toxicity were observed at approximately 3 times the MRHD based on BSA comparison.” (opens the prescribing information at this quote)

“There are insufficient data on the presence of bepirovirsen or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Bepirovirsen was detectable in the milk of lactating mice without an effect on offspring (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.” (opens the prescribing information at this quote)

“Although bepirovirsen was detected in the milk of lactating mice (on LD 10), systemic exposure of bepirovirsen in the offspring via milk was negligible.” (opens the prescribing information at this quote)

Nonclinical toxicology: carcinogenesis, mutagenesis, and impairment of fertility

“In a 2-year carcinogenicity study in mice, bepirovirsen sodium was administered by subcutaneous injection weekly at doses of 3, 10, and 30 mg/kg (approximately 0.05, 0.2, and 0.5 times the RHD, respectively, based on BSA comparison).” (opens the prescribing information at this quote)

“In male mice, statistically significant increases in tumor incidences were observed compared to controls in liver (hepatocellular carcinomas at ≥10 mg/kg; hepatocellular adenomas, combined hepatocellular adenomas/carcinomas, hemangiosarcomas, and combined hemangiosarcomas/hemangiomas at 30 mg/kg), in stomach (adenomas and combined adenomas/adenocarcinomas at 30 mg/kg), and at the injection sites (fibrosarcomas at 30 mg/kg).” (opens the prescribing information at this quote)

“In female mice, hepatocellular adenoma and combined hepatocellular adenoma/carcinoma were increased at 30 mg/kg.” (opens the prescribing information at this quote)

“Increased tumor findings have been observed in 2-year carcinogenicity studies in mice dosed subcutaneously with phosphorothioate ASO class drugs; the clinical relevance is unknown.” (opens the prescribing information at this quote)

“Bepirovirsen did not exhibit a genotoxic potential in a battery of studies, including an in vitro bacterial reverse mutation (Ames) test, mammalian cell chromosomal aberration test and an in vivo micronucleus test in mice.” (opens the prescribing information at this quote)

“No adverse effects on male or female mating or fertility were observed following subcutaneous administration of bepirovirsen to mice up to 0.7 times the MRHD (based on BSA comparison).” (opens the prescribing information at this quote)

Overdosage

“Single doses of HIBSAGO 600 mg (2 times the recommended dose) were administered subcutaneously in a clinical trial to 5 healthy adults. Two participants developed tolerability issues at this dose, with symptoms including headache, nausea, vomiting, myalgia, and dizziness which lasted 24 to 48 hours despite symptomatic treatment.” (opens the prescribing information at this quote)

“There is no specific treatment for an overdose with HIBSAGO. If overdose occurs, the patient should be treated supportively with appropriate monitoring.” (opens the prescribing information at this quote)

“Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.” (opens the prescribing information at this quote)

Dosing and administration

Table 5. Usual dosing regimens

Generic NameUsual Adult DoseUsual Pediatric DoseAvailability
BepirovirsenWeeks 1 and 2: “The recommended dosage of HIBSAGO is 300 mg (administered as two 150 mg subcutaneous injections) twice a week allowing 3 or 4 days between each dose.”Weeks 3 to 24: “The recommended dosage of HIBSAGO is 300 mg (administered as two 150 mg subcutaneous injections) once a week on the same day each week.”Maximum duration: “The maximum recommended duration of HIBSAGO treatment is 24 weeks”Route: “HIBSAGO is for subcutaneous use only”“The safety and effectiveness of HIBSAGO have not been established in patients less than 18 years of age.”“Injection: 150 mg/mL of bepirovirsen as a clear, colorless to yellow sterile solution with no visible particulates in a single-dose prefilled glass syringe within a safety syringe device.”“HIBSAGO injection is supplied as 150 mg/mL, single-dose, prefilled glass syringe with attached 27-gauge, 0.5 inch (12.7 mm) needle with a needle guard in cartons of 2 (NDC 0173-0941-39).”“Each single-dose prefilled syringe delivers 150 mg of bepirovirsen in 1 mL of solution.”

See the current prescribing information for full details.

Combination with nucleos(t)ide analog therapy and laboratory monitoring

“HIBSAGO must be used in combination with NrtI therapy. Refer to the NrtI prescribing information for additional information.” (opens the prescribing information at this quote)

“HIBSAGO therapy should be prescribed only when appropriate laboratory monitoring can be performed to manage the treatment regimen. Close laboratory monitoring is required to assess for toxicities that may necessitate dose modification, treatment interruption, or permanent discontinuation of HIBSAGO” (opens the prescribing information at this quote)

Early cessation at treatment week 12

“Early cessation of HIBSAGO may be considered in patients who have not achieved HBsAg <1 IU/mL by Treatment Week 12” (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. 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)

Dosage modification by ALT and total bilirubin

ALT and total bilirubinDosageALT and total bilirubin monitoring frequency
ALT <3x ULN“No dosage adjustments required”“Weekly through Week 12 and every other week from Weeks 12 through 24”
Total bilirubin <1.5x ULN, ALT <10x ULN“No dosage adjustments required”“Weekly through Week 12 and every other week from Weeks 12 through 24”
Total bilirubin <1.5x ULN, ALT ≥10x to <12x ULN“No dosage adjustments required”“Increase monitoring to twice weekly until ALT is on a downward trajectory”
Total bilirubin <1.5x ULN, ALT ≥12x ULN“Pause treatment”“When ALT<10x ULN, resume treatment at 150 mg once a week. If ALT continues to decline, increase dosage to 300 mg once a week.”“Increase monitoring to twice weekly until ALT is on a downward trajectory”
Total bilirubin <1.5x ULN, ALT ≥10x ULN for ≥4 weeks“Permanently discontinue treatment”“Twice weekly until ALT is on a downward trajectory and then as clinically indicated”
Total bilirubin ≥1.5 to <2x ULN, ALT ≥3x ULN“Pause treatment”“When ALT <10x ULN and total bilirubin <1.5x ULN, resume treatment at 150 mg once a week. If ALT is on a downward trajectory, increase dosage to 300 mg once a week.”“Increase monitoring to twice weekly until ALT is on a downward trajectory”
Total bilirubin ≥2x ULN, ALT ≥3x ULN“Permanently discontinue treatment”“Twice weekly until ALT is on a downward trajectory and then as clinically indicated”

Notes to the ALT and total bilirubin dosage modifications

“If ALT or total bilirubin has increased markedly from the previous assessment, repeat laboratory testing and review the results before giving the next dose of HIBSAGO, even if the values have not yet reached the thresholds that require treatment interruption or discontinuation.” (opens the prescribing information at this quote)

“In all patients with abnormal values at the time of HIBSAGO discontinuation, obtain ALT and total bilirubin values at 4, 12, and 24 weeks post-treatment to assess recovery of ALT values to within the normal range, as appropriate.” (opens the prescribing information at this quote)

Dosage modification by platelet count

Platelet count (x 10^9/L)DosagePlatelet monitoring frequency
≥100“No dosage adjustment required”“Weekly”
75 to <100“Pause treatment”“When platelet count ≥100 x 109/L, resume treatment at 300 mg once a week”“Weekly”
50 to <75“Pause treatment”“When platelet count ≥100 x 109/L, resume treatment at 300 mg once a week”“Every 2-3 days until 3 consecutive platelet counts ≥75 x 109/L”
25 to <50“Permanently discontinue treatment”“Every 2-3 days until 3 consecutive platelet counts ≥75 x 109/L”
<25“Permanently discontinue treatment”“Daily until 2 consecutive platelet counts ≥25 x 109/L”

Notes to the platelet count dosage modifications

“If platelet count decreases by ≥30% between consecutive readings, repeat and review platelet count before administering further doses of HIBSAGO, even if platelet count is ≥100 x 109/L.” (opens the prescribing information at this quote)

“In all patients with abnormal values at the time of HIBSAGO discontinuation, obtain repeat platelet counts 4 and 12 weeks post-treatment to assess for platelet count recovery, as appropriate.” (opens the prescribing information at this quote)

Dosage modification by eGFR

eGFRDosageeGFR monitoring frequency
No significant change from baseline“No dosage adjustment required”“Monitor eGFR every other week through Week 24”
Reduced by ≥30% from pretreatment levels for ≥2 consecutive readings“Pause treatment”“When eGFR increases to within 15% of pretreatment levels, resume treatment at 300 mg once a week.”“Monitor weekly until eGFR stabilizes or returns to pretreatment levels”

Note to the eGFR dosage modifications

“In all patients with abnormal values at the time of HIBSAGO discontinuation, obtain eGFR at 4 weeks and 12 weeks post-treatment to monitor for renal function recovery, as appropriate.” (opens the prescribing information at this quote)

Dosage in renal and hepatic impairment

“No dosage adjustment is recommended in patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73m2) [see Clinical Pharmacology (12.3)]. Insufficient data are available on the safety of HIBSAGO in patients with moderate or severe renal impairment or end stage renal disease (eGFR less than or equal to 59 mL/min/1.73m2). HIBSAGO can cause worsening renal function [see Warnings and Precautions (5.3)].” (opens the prescribing information at this quote)

“The safety and efficacy of HIBSAGO in patients with cirrhosis have not been established. The use of HIBSAGO is contraindicated in chronic hepatitis B patients with acute hepatic impairment, or cirrhosis who have mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Contraindications (4), Clinical Pharmacology (12.3)].” (opens the prescribing information at this quote)

Missed doses

“If a dose of HIBSAGO is missed at any time during treatment (Weeks 1-24), the missed dose must be administered as soon as possible, unless the next scheduled dose is due in less than three days, in which case the missed dose must be skipped and the next dose administered as scheduled.” (opens the prescribing information at this quote)

Completion of treatment: nucleos(t)ide analog continuation and criteria for stopping it

“HIBSAGO must be stopped upon completion of 24 weeks of treatment, and patients must remain on their NrtI therapy for at least an additional 24 weeks. Following the 24 weeks of further NrtI treatment, stopping NrtI therapy can be considered in those patients who:” (opens the prescribing information at this quote)

“are hepatitis B e-antigen (HBeAg) negative,” (opens the prescribing information at this quote)

“have HBV DNA <LLOQ (lower limit of quantification, defined as <20 IU/mL), HBsAg not detectable (LOD = 0.05 IU/mL), and alanine aminotransferase (ALT) values ≤2x upper limit of normal (ULN), and” (opens the prescribing information at this quote)

“do not need the nucleos(t)ide analog reverse transcriptase inhibitor therapy to treat Human Immunodeficiency Virus (HIV) co-infection” (opens the prescribing information at this quote)

“If NrtI therapy is stopped, frequent monitoring of HBsAg, HBV DNA, and hepatic function is recommended for at least one year following NrtI therapy cessation, with routine monitoring as clinically indicated afterwards” (opens the prescribing information at this quote)

Supervised first dose and self-administration

“HIBSAGO must be administered under the guidance and supervision of a healthcare provider for the initial dose to ensure proper injection technique.” (opens the prescribing information at this quote)

“Patients or caregivers may administer HIBSAGO after their healthcare provider determines that it is appropriate and with medical follow-up, including laboratory testing. Healthcare providers must provide proper training in subcutaneous injection technique before the patient or caregivers can administer HIBSAGO” (opens the prescribing information at this quote)

“Train patients and caregivers on the importance of proper subcutaneous administration technique, the necessity of rotating injection sites and how to use the prefilled syringe. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use HIBSAGO” (opens the prescribing information at this quote)

Preparation, injection sites, and the two-syringe dose

“Ensure HIBSAGO has been at room temperature (below 86°F [30°C]) for a minimum of 30 minutes prior to injection” (opens the prescribing information at this quote)

“Prior to administration, visually inspect the window of the prefilled syringes for particulate matter or discoloration. HIBSAGO injection should be clear and colorless to yellow and free of visible particulate matter. Do not use HIBSAGO injection if the product exhibits discoloration, cloudiness, or particulate matter. Do not shake the HIBSAGO syringe. Do not use the syringes if they have been dropped or damaged.” (opens the prescribing information at this quote)

“Inject into the thigh or abdomen, avoiding the 2 inches (5 cm) around the navel. The outer area of the upper arm can also be used if a caregiver administers the subcutaneous injections.” (opens the prescribing information at this quote)

“For a 300 mg dose, administer 2 x 150 mg pre-filled syringes, inject one right after the other. Choose a different injection site for each injection, at least 2 inches (5 cm) from the other injection sites” (opens the prescribing information at this quote)

“For a 150 mg dose administer 1 x 150 mg pre-filled syringe injection.” (opens the prescribing information at this quote)

“Never give injections into areas where the skin is tender, bruised, red, or hard. Rotate injection sites to reduce the risk of injection site reactions” (opens the prescribing information at this quote)

Solution, excipients, and syringe

“HIBSAGO injection for subcutaneous use is a sterile, preservative-free, clear, colorless to yellow solution with no visible particulates.” (opens the prescribing information at this quote)

“HIBSAGO injection is supplied as two, 1-mL, single-dose, prefilled syringes with a 0.5 inch (12.7 mm), 27-gauge, stainless steel needle assembled with a needle guard.” (opens the prescribing information at this quote)

“Each 1 mL delivers 150 mg bepirovirsen, equivalent to 159 mg of bepirovirsen sodium, in 1 mL water for injection and may contain hydrochloric acid or sodium hydroxide to adjust to pH 8.” (opens the prescribing information at this quote)

“The syringes are not made with natural rubber latex.” (opens the prescribing information at this quote)

Storage and handling

“Prior to Dispensing: Store in a refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze. Store in the original carton to protect from light. Do not shake.” (opens the prescribing information at this quote)

“Following Dispensing: Store HIBSAGO at room temperature up to 86°F (30°C) for 12 weeks. Do not freeze.” (opens the prescribing information at this quote)

“Discard if the expiry date has passed, or it has been 12 weeks since carton was received, whichever comes first.” (opens the prescribing information at this quote)

“HIBSAGO injection must be administered within 6 hours once removed from the carton. Discard if not administered within 6 hours.” (opens the prescribing information at this quote)

Effectiveness

Table 6. Comparative clinical trials

Study and Drug RegimenStudy Design and DemographicsStudy Size and DurationEnd PointsResults
B-Well 1 (NCT05630807): “Participants were randomized 2:1 to receive HIBSAGO for 24 weeks (300 mg, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24), or placebo, together with their background NrtI therapy.”“Each dose of HIBSAGO was administered as two 150 mg subcutaneous injections into the abdomen, thigh, and/or outer area of upper arms.”“From Week 25 to 48, participants continued to receive their NrtI therapy without HIBSAGO or placebo.”“At Week 48, participants who met the prespecified NrtI cessation eligibility criteria discontinued NrtI therapy.”“The efficacy of HIBSAGO in the treatment of chronic HBV infection was evaluated in two multi-center, Phase 3, randomized, double-blind, placebo-controlled trials with identical designs (B-Well 1 [NCT05630807] and B-Well 2 [NCT05630820]).”“The randomization was stratified by HBsAg levels at baseline (HBsAg ≤ 1,000 IU/mL or >1,000 IU/mL to ≤3,000 IU/mL).”“All participants were aged ≥18 years, had documented chronic HBV infection for ≥6 months, were receiving stable NrtI therapy (defined as no changes due to loss of virologic control for ≥6 months before the start of the trial and no plans for changes over the duration of the trial), and had serum HBsAg >100 to ≤3,000 IU/mL at screening, HBV DNA <90 IU/mL, and ALT ≤2X the upper limit of normal.”“Participants could be either HBeAg-positive or HBeAg-negative at baseline.”“Participants were excluded from the trial if they had a history, suspicion, or evidence of cirrhosis; co-infection with HCV, HIV, or HDV; history or evidence of potential vasculitis; eGFR ≤60 mL/min/1.73m2; or platelet count <140 x 109/L.”“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”“58% were in Asia, 25% were in Europe, 10% were in Latin America, and 7% were in US and Canada”“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”“91% had ALT ≤ULN at baseline; 92% were HBeAg negative at baseline”“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.”“In Trial B-Well 1, a total of 981 participants were randomized (2:1) to receive either HIBSAGO or placebo.”“In the full analysis set (FAS) of 978 participants who received at least one dose of HIBSAGO or placebo”“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.”Primary: “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.”Key secondary: “The first key secondary endpoint was assessed by applying the same criteria to participants with baseline HBsAg ≤1,000 IU/mL.”“The second key secondary efficacy endpoint was sustained suppression of HBV DNA (<LLOQ), at 24 weeks after discontinuation of all chronic HBV treatment in the absence of rescue medication in participants with baseline HBsAg ≤3,000 IU/mL.”“The third key secondary endpoint was assessed by applying the same criteria of sustained suppression of HBV DNA (<LLOQ) to participants with baseline HBsAg ≤1,000 IU/mL.”Primary endpoint, Hibsago, n/N (%): “127/650 (20)”Primary endpoint, placebo, n/N (%): “0/328 (0)”Common rate difference, % (95% CI): “17 (14.6, 20.3)”p-value: “<0.0001”First key secondary endpoint, Hibsago, n/N (%): “105/426 (25)”First key secondary endpoint, placebo, n/N (%): “0/214 (0)”Rate difference, % (95% CI): “25 (20.8, 29.0)”p-value: “<0.0001”Second key secondary endpoint, Hibsago, n/N (%): “151/650 (23)”Second key secondary endpoint, placebo, n/N (%): “0/328 (0)”Common rate difference, % (95% CI): “21 (17.9, 24.0)”p-value: “<0.0001”Third key secondary endpoint, Hibsago, n/N (%): “124/426 (29)”Third key secondary endpoint, placebo, n/N (%): “0/214 (0)”Rate difference, % (95% CI): “29 (25.0, 33.6)”p-value: “<0.0001”“Within both trials, the primary and key secondary endpoints were met.”
B-Well 2 (NCT05630820): “Participants were randomized 2:1 to receive HIBSAGO for 24 weeks (300 mg, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24), or placebo, together with their background NrtI therapy.”“Each dose of HIBSAGO was administered as two 150 mg subcutaneous injections into the abdomen, thigh, and/or outer area of upper arms.”“From Week 25 to 48, participants continued to receive their NrtI therapy without HIBSAGO or placebo.”“At Week 48, participants who met the prespecified NrtI cessation eligibility criteria discontinued NrtI therapy.”“The efficacy of HIBSAGO in the treatment of chronic HBV infection was evaluated in two multi-center, Phase 3, randomized, double-blind, placebo-controlled trials with identical designs (B-Well 1 [NCT05630807] and B-Well 2 [NCT05630820]).”“The randomization was stratified by HBsAg levels at baseline (HBsAg ≤ 1,000 IU/mL or >1,000 IU/mL to ≤3,000 IU/mL).”“All participants were aged ≥18 years, had documented chronic HBV infection for ≥6 months, were receiving stable NrtI therapy (defined as no changes due to loss of virologic control for ≥6 months before the start of the trial and no plans for changes over the duration of the trial), and had serum HBsAg >100 to ≤3,000 IU/mL at screening, HBV DNA <90 IU/mL, and ALT ≤2X the upper limit of normal.”“Participants could be either HBeAg-positive or HBeAg-negative at baseline.”“Participants were excluded from the trial if they had a history, suspicion, or evidence of cirrhosis; co-infection with HCV, HIV, or HDV; history or evidence of potential vasculitis; eGFR ≤60 mL/min/1.73m2; or platelet count <140 x 109/L.”“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”“59% were in Asia, 27% were in Europe, 6% were in US and Canada, 4% were in Latin America, and 4% were in Oceania”“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”“93% had ALT ≤ULN at baseline; 92% were HBeAg negative at baseline”“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.”“In Trial B-Well 2, a total of 857 participants were randomized (2:1) to receive either HIBSAGO or placebo.”“In the FAS of 856 participants who received at least one dose of HIBSAGO or placebo”“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.”Primary: “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.”Key secondary: “The first key secondary endpoint was assessed by applying the same criteria to participants with baseline HBsAg ≤1,000 IU/mL.”“The second key secondary efficacy endpoint was sustained suppression of HBV DNA (<LLOQ), at 24 weeks after discontinuation of all chronic HBV treatment in the absence of rescue medication in participants with baseline HBsAg ≤3,000 IU/mL.”“The third key secondary endpoint was assessed by applying the same criteria of sustained suppression of HBV DNA (<LLOQ) to participants with baseline HBsAg ≤1,000 IU/mL.”Primary endpoint, Hibsago, n/N (%): “106/570 (19)”Primary endpoint, placebo, n/N (%): “0/286 (0)”Common rate difference, % (95% CI): “13 (10.4, 16.1)”p-value: “<0.0001”First key secondary endpoint, Hibsago, n/N (%): “95/342 (28)”First key secondary endpoint, placebo, n/N (%): “0/179 (0)”Rate difference, % (95% CI): “28 (23.3, 32.8)”p-value: “<0.0001”Second key secondary endpoint, Hibsago, n/N (%): “132/570 (23)”Second key secondary endpoint, placebo, n/N (%): “0/286 (0)”Common rate difference, % (95% CI): “18 (15.1, 21.3)”p-value: “<0.0001”Third key secondary endpoint, Hibsago, n/N (%): “113/342 (33)”Third key secondary endpoint, placebo, n/N (%): “0/179 (0)”Rate difference, % (95% CI): “33 (28.3, 38.2)”p-value: “<0.0001”“Within both trials, the primary and key secondary endpoints were met.”

Abbreviations: ALT=alanine aminotransferase; CHB=chronic hepatitis B; CI=confidence interval; eGFR=estimated glomerular filtration rate; FAS=full analysis set; HBeAg=hepatitis B e-antigen; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HDV=hepatitis D virus; HIV=human immunodeficiency virus; LLOQ=lower limit of quantification; LOD=limit of detection; NrtI=nucleos(t)ide analog reverse transcriptase inhibitor; ULN=upper limit of normal

Statistical methods for the primary and key secondary endpoints

“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)

“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)

“Blips in the Week 72 analysis window were permitted for the primary and key secondary endpoint analyses.” (opens the prescribing information at this quote)

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

Nucleos(t)ide analog cessation and restart criteria

“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)

“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)

Subgroups with lower response in the pooled population

“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)

“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)

Response by HBV genotype and baseline HBsAg in the pooled population

“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)

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)

Durability of response at weeks 72 and 96 after nucleos(t)ide analog cessation

“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)

“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)

“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 in B-Well 1 and B-Well 2

Trial and baseline HBsAg stratumBaseline nucleotide polymorphisms, % (n/N)Treatment-emergent nucleotide mutations, % (n/N)
B-Well 1, baseline HBsAg ≤3,000 IU/mL“6 (7/123)”“5 (2/42)”
B-Well 2, baseline HBsAg ≤3,000 IU/mL“7 (7/104)”“6 (2/31)”
B-Well 1, baseline HBsAg ≤1,000 IU/mL“3 (2/69)”“5 (1/22)”
B-Well 2, baseline HBsAg ≤1,000 IU/mL“12 (6/50)”“0 (0/10)”

Phenotypic susceptibility of binding-site variants

“Cell culture based phenotypic testing of baseline and treatment emergent variants identified in HIBSAGO clinical trials indicated 1.2- to 4.1-fold reductions in susceptibility relative to wild-type based on HBsAg inhibition in primary human hepatocytes.” (opens the prescribing information at this quote)

“Approximate EC50 fold-changes for individual variants relative to wild-type were: G1588A (2.8-fold), C1589A (4.1-fold), T1590A (1.8-fold), T1590G (3.0-fold), C1595T (2.3-fold), and C1600T (1.2-fold). The clinical impact of reduced susceptibility to HIBSAGO in these variants is unknown.” (opens the prescribing information at this quote)

“Deep mutational scanning identified resistance-conferring mutations predominantly within the central DNA gap region of the bepirovirsen target sequence; mutations in the 2’-MOE-modified wing regions had minimal effect on susceptibility.” (opens the prescribing information at this quote)

Registered primary outcome measure of B-Well 1 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 primary outcome measure of B-Well 2 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)

Primary outcome and results in the trial 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

“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

“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) 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

References

  1. ClinicalTrials.gov NCT05630807 (opens in a new tab)
  2. ClinicalTrials.gov NCT05630820 (opens in a new tab)
  3. Hibsago prescribing information (2026) (opens in a new tab)
  4. Hou et al. (2026a) (opens in a new tab)