In chronic hepatitis B

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HIBSAGO (bepirovirsen)

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An FDA-designated breakthrough therapy approved for treatment of chronic hepatitis B in noncirrhotic adults already on NA therapy with HBsAg ≤3,000 IU/mL.1,2 HIBSAGO is the first and only 6-month finite treatment, used with nucleos(t)ide analog (NA), with the potential for functional cure.

Functional cure is evaluated at 18 months: after 6 months of HIBSAGO + NA, 6 months of NA alone, and 6 months without treatment for eligible patients who discontinue NA therapy.2-4*†

 

NA=nucleos(t)ide analog for treatment of chronic hepatitis B, herewith used interchangeably with Nrtl.

HIBSAGO functional cure rate of 19% + NA versus 0% with placebo + NA

In a pooled analysis from B-Well 1 and B-Well 2, the functional cure rate at 72 weeks with HIBSAGO + NA was 19% (n=233/1,220) vs 0% with placebo + NA (n=0/614) in noncirrhotic participants who had HBsAg ≤3,000 IU/mL.2,4 Results are descriptive.

 

PRIMARY ENDPOINT

For the B-Well 1 trial, 20% (n=127/650) of HIBSAGO-treated participants achieved functional cure compared to 0% (n=0/328) who received placebo + NA in those with baseline HBsAg ≤3,000 IU/mL (common rate difference‡: 17% [95% CI: 14.6–20.3]). For the B-Well 2 trial, 19% (n=106/570) of HIBSAGO-treated participants achieved functional cure compared to 0% (n=0/286) who received placebo + NA with baseline HBsAg ≤3,000 IU/mL (common rate difference‡: 13% [95% CI: 10.4–16.1]). p<0.0001§ for both comparisons.2,4

*Functional cure was defined as HBsAg loss (LOD=0.05 IU/mL) and undetectable HBV DNA (<LLOQ), sustained for ≥24 weeks off all HBV treatment, with or without hepatitis B surface antibodies present.2,4

†HIBSAGO was stopped after completion of 24 weeks treatment, and adults continued NA therapy for an additional 24 weeks. To be eligible for NA cessation, participants had to have no evidence of cirrhosis at Week 36, have HBV DNA <LLOQ and HBsAg not detected from Weeks 24–46 (allowing for single blips to any level, defined as transiently quantifiable HBV DNA ≥LLOQ or detected HBsAg at a single visit) in the absence of rescue medication.2

‡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.2,4

§Based on 2-sided p value (exact Cochran-Mantel Haenszel).2

Study design

Study methodology

  • ‖

    Stable NA therapy was defined as no change due to loss of virologic control for ≥6 months before the start of the study and no plans for changes over the duration of the study.2,4

  • Allowing for single blips to any level as defined as transiently quantifiable HBV DNA (≥LLOQ) or detected HBsAg at a single visit.2

Visual representation of B-Well 1 and B-Well 2 clinical trial results

  • Functional cure was defined as HBsAg loss (LOD=0.05 IU/mL) and undetectable HBV DNA (<LLOQ), sustained for ≥24 weeks off all HBV treatment, with or without hepatitis B surface antibodies present.2,4
  • 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 method2,4
  • Based on 2-sided p value (exact Cochran-Mantel Haenszel)2
  • The efficacy and safety of HIBSAGO in the treatment of chronic HBV infection have been evaluated across two Phase 3, placebo-controlled, randomized studies, B-Well 1 and B-Well 22,4
  • To be eligible for NA cessation in B-Well 1 and B-Well 2, participants had to have no evidence of cirrhosis at Week 36, have HBV DNA <LLOQ and HBsAg not detected from Weeks 24 to 46 (allowing for single blips to any level) in the absence of rescue medication (defined as any medication with proven anti-HBV activity newly initiated for the purpose of HBV control), be HBeAg negative with ALT values ≤2x ULN at Week 46, and have remained on stable NA therapy for the preceding 48 weeks. HIBSAGO must be stopped upon completion of 24 weeks of treatment, and patients must remain on their NA therapy for an additional 24 weeks2,4
Missed dose icon

Key safety data

The most common adverse reactions (≥10%), excluding laboratory abnormalities, reported with HIBSAGO + NA vs placebo + NA, respectively, included injection site reactions (57% vs 15%), pyrexia (20% vs 4%), fatigue (16% vs 8%), and headache (14% vs 12%).2

Selected laboratory abnormalities (worsened from baseline) reported in participants in the B-Well 1 and B-Well 2 trials (Weeks 1–36)2*

Selected Laboratory Abnormalities (Worsened from Baseline) Reported in Participants in B-Well 1 and B-Well 2 Trials (Weeks 1-36)
Lab categories HIBSAGO + NA (N=1,223) Placebo + NA (N=611)
ALT
≥3x ULN to <5x ULN 10% <1%
≥5x ULN to <10x ULN 8% 0
≥10x ULN to <20x ULN 4% 0
≥20x ULN 2% <1%
AST
≥3x ULN to <5x ULN 6% <1%
≥5x ULN to <10x ULN 4% <1%
≥10x ULN to <20x ULN 1% <1%
≥20x ULN <1% 0
Total bilirubin
≥ULN to <1.5x ULN 8% 11%
≥1.5x ULN to <2x ULN 2% 2%
≥2x ULN <1% <1%
Platelets (x10⁹/L)
≥100 to <140 37% 7%
≥75 to <100 8% <1%
≥50 to <75 2% <1%
≥25 to <50 <1% 0
<25 <1% 0
ANC cells/mm³
≥500 to <1,000 8% 3%
≥100 to <500 1% <1%
<100 0 0
eGFR
≥15% to <30% decline from baseline 51% 30%
≥30% to <50% decline from baseline 17% 6%
≥50% decline from baseline 1% <1%
uACR
≥0.3 mg/mg 2% 1%

*Each participant is only counted once per parameter with the laboratory value that represents their largest change from baseline in Weeks 1–36.

  • ALT increased: During the first 24 weeks, <1% (n=1) of HIBSAGO recipients had ALT ≥3x ULN with bilirubin ≥2x ULN and permanently discontinued treatment. Three other participants also permanently discontinued treatment because of ALT ≥10x ULN for 4 or more weeks, and 53 (4%) paused treatment due to ALT increases2
  • Decreased platelet counts: During the first 24 weeks, 2 participants treated with HIBSAGO had serious adverse reactions of thrombocytopenia, with platelet counts <50 x 109/L. Both participants recovered with corticosteroid treatment and permanent discontinuation of HIBSAGO. In total, 8 (<1%) participants met permanent discontinuation criteria, and 114 (9%) participants paused treatment due to platelet declines. In the pivotal clinical trials, the maximum change from baseline in platelet count in the HIBSAGO group occurred at Week 24, with a mean (SD) change from baseline of -68 x 109/L (40.7) or -28.1% (13.79), from a baseline of 233 x 109/L. The mean platelet count in the HIBSAGO group recovered to within 5% of baseline values by Week 60 (36 weeks after last dose of HIBSAGO)2
  • eGFR decreased: 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% (1 participant) experienced such declines more than 24 weeks after completion of HIBSAGO treatment. No participant met criteria for permanent discontinuation of HIBSAGO treatment based on decreased renal function, but 28 (2%) participants paused treatment because of decreased renal function. In the pivotal clinical trials, the maximum change from baseline in eGFR in the HIBSAGO group occurred at Week 25, with a mean (SD) change from baseline of -10 mL/min/1.73 m2 (9.96) or -10% (10.28), from a baseline of 100.8 mL/min/1.73 m2. The mean eGFR in the HIBSAGO group recovered to within 5% of baseline values by Week 36 (12 weeks after last dose of HIBSAGO)2
  • Decrease in neutrophil counts: During the first 24 weeks, 27 (2%) 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. 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. 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)2

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ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase; CI=confidence interval; DNA=deoxyribonucleic acid; eGFR=estimated glomerular filtration rate; FDA=US Food and Drug Administration; HBeAg=hepatitis B e-antigen; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; LLOQ=lower limit of quantification; LOD=limit of detection; NrtI=nucleos(t)ide analog reverse transcriptase inhibitor; SD=standard deviation; uACR=urine albumin-creatinine ratio; ULN=upper limit of normal.

INDICATION & IMPORTANT SAFETY INFORMATION

INDICATION

IMPORTANT SAFETY INFORMATION

INDICATION

HIBSAGO is indicated in combination with nucleos(t)ide analog reverse transcriptase inhibitor (NrtI) therapy to treat chronic hepatitis B virus (HBV) infection in adults without cirrhosis who have been on NrtI therapy for ≥6 months with suppressed HBV DNA and who have HBV surface antigen (HBsAg) levels ≤3,000 IU/mL as determined by an FDA-authorized test.

IMPORTANT SAFETY INFORMATION

WARNING: ON-TREATMENT HEPATIC FLARES AND THROMBOCYTOPENIA

On-Treatment Hepatic Flares

HIBSAGO may cause on-treatment hepatic flares with increases in alanine aminotransferase (ALT) of >20-40x upper limit of normal (ULN) associated with decline in HBsAg. Some cases were associated with hyperbilirubinemia. Most occurred within the first 12 weeks and resolved when treatment was interrupted or discontinued. Do not initiate HIBSAGO in patients with evidence of acute hepatic impairment or cirrhosis. ALT and total bilirubin must be measured prior to treatment and frequently monitored during treatment. Treatment interruption, followed by dose reduction or discontinuation, may be necessary based on liver laboratory results.

Thrombocytopenia

HIBSAGO may cause reductions in platelet counts that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening. Obtain platelet count prior to treatment; HIBSAGO is contraindicated in patients with platelet count <100 x 10⁹/L. Monitor platelet counts weekly during treatment and more frequently if platelet count falls <75 x 109/L. Do not re-dose unless platelet count returns to ≥100 x 10⁹/L. Permanently discontinue HIBSAGO if platelet count falls <50 x 10⁹/L.

CONTRAINDICATIONS

HIBSAGO is contraindicated in patients:

  • with acute hepatic impairment or cirrhosis who have mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C).

  • with a platelet count <100 x 109/L prior to initiation of treatment.

WARNINGS AND PRECAUTIONS

On-Treatment Hepatic Flares

Increases in ALT ≥3x ULN to 69x ULN were observed during treatment with HIBSAGO, most within the first 12 weeks. Isolated cases of ALT increases associated with an increase in total bilirubin resolved when treatment was permanently discontinued.

Thrombocytopenia

In addition to sudden and unpredictable thrombocytopenia, a gradual, dose-dependent decline in platelet count was observed in most patients that continued to worsen while on HIBSAGO. If a patient develops signs or symptoms of thrombocytopenia, pause HIBSAGO and obtain a platelet count as soon as possible. Instruct patients to report any symptoms of thrombocytopenia to their healthcare provider immediately. Consider the risks and benefits of treatment with HIBSAGO when treating patients who may be particularly susceptible to platelet count decreases.

Worsening Renal Function

Mean estimated glomerular filtration rate (eGFR) declined within 4 weeks of initiation and continued to decline during treatment. These changes were generally reversible after treatment discontinuation.

Obtain eGFR and urine albumin-creatinine ratio (uACR) in all patients prior to initiation of treatment. Monitor eGFR frequently during and after treatment; treatment interruption or discontinuation may be necessary. Although no cases of glomerulonephritis were observed with HIBSAGO, glomerulonephritis has been observed with other antisense oligonucleotides; if suspected or confirmed, permanently discontinue HIBSAGO.

Inflammatory and Immune Effects

Influenza-like symptoms, laboratory test changes (eg, 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.

Consider the risks and benefits of HIBSAGO in patients who may be susceptible to inflammatory and immune effects, including solid organ transplant recipients, patients with autoimmune hepatitis, patients with a history of or conditions associated with vasculitis, or extrahepatic disorders related to HBV immune-mediated effects. If signs and symptoms suggestive of vasculitis/immune-associated events occur, and no alternative cause is identified, permanently discontinue treatment with HIBSAGO.

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. Ensure injection sites are rotated from one week to the next and that the two injections making up each dose are separated by at least 2 inches (5 cm). Never inject into areas where the skin is tender, bruised, red, or hard.

Post-Treatment Exacerbations of HBV Infection After NrtI Discontinuation

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 for at least one year to detect acute exacerbations of HBV infection and the possible need for resumption of HBV treatment.

Risk of Human Immunodeficiency Virus-1 (HIV-1) Virologic Failure in Patients with HBV/HIV-1 Coinfection Who Discontinue NrtI Therapy

Patients who are taking NrtI for HIV-1 and HBV coinfection must not stop taking their NrtI unless an HIV healthcare provider has directed them to do so.

Risk of Hepatitis Flare in Patients with HBV/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.

Unknown Effect on Preventing Transmission of HBV

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.

ADVERSE REACTIONS

The most common adverse reactions (≥10%), excluding laboratory abnormalities, reported with HIBSAGO included injection site reactions, pyrexia, fatigue, and headache.

Selected laboratory abnormalities worsened from baseline, including but not limited to, increases in ALT and total bilirubin, decreases in platelets and eGFR.

DRUG INTERACTIONS

  • Monitor patients for signs of bleeding and thrombocytopenia if HIBSAGO is taken concomitantly with anticoagulants, antiplatelets, or drugs that decrease platelet count.
  • Monitor patients for signs of worsening renal function during concomitant administration of HIBSAGO with drugs that may impair renal function.
  • 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.

USE IN SPECIFIC POPULATIONS

Pregnancy and Lactation

There are insufficient data on HIBSAGO use in pregnancy or during breastfeeding. Consider the benefits of breastfeeding together with the mother’s clinical need for HIBSAGO.

Pediatric Use

HIBSAGO’s safety and effectiveness have not been established in patients under 18 years of age.

Renal Impairment

HIBSAGO can cause worsening renal function. No dosage adjustment is recommended for mild renal impairment. Data are insufficient for moderate or severe renal impairment or end-stage renal disease (ESRD).

 

Please click to see full Prescribing Information, including Boxed Warning, for HIBSAGO.

To report SUSPECTED ADVERSE REACTIONS, contact GSK at gsk.public.reportum.com or 1-888-825-5249, or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References

  1. FDA Breakthrough Therapy. US Food and Drug Administration. January 4, 2018. Accessed September 10, 2026. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy

  2. HIBSAGO. Prescribing Information. GSK; 2026.

  3. Yuen MF, Chen DS, Dusheiko GM, et al. Hepatitis B virus infection. Nat Rev Dis Primers. 2018;4:18035.

  4. Hou J, Lim SG, Buti M, et al; B-Well Study Group. Phase 3 results of bepirovirsen treatment for chronic hepatitis B virus infection. N Engl J Med. 2026;394(24):2395-2406. Figures and tables copyright © (2026) Massachusetts Medical Society. Adapted with permission from Massachusetts Medical Society.