Hibsago (bepirovirsen)

Published estimates of the number of persons living with hepatitis B virus (HBV) infection in the United States range from 580,000 to 2.4 million. In the National Health and Nutrition Examination Survey (NHANES), 0.2% of persons aged 6 years and older, an estimated 660,000 persons, had HBV infection, and 49.8% of them were aware of it; non-US-born persons accounted for 73.6% of those infected. Modeling studies estimated 1.8 million HBV-positive individuals in the United States in 2020 (prevalence 0.55%) and 1.7 million in the United States and Puerto Rico (prevalence 0.50%). In the 2020 model, approximately 334,800 infections (18%) were diagnosed, and 90,500 of 534,100 individuals eligible for treatment (just under 17%) were treated; 35,000 of the 36,400 new chronic infections in 2020 (96%) were among immigrants.

During 2023, 17,650 newly reported cases of chronic hepatitis B were reported to CDC by 44 states and the District of Columbia (6.1 cases per 100,000 population); the rate among non-Hispanic Asian and Pacific Islander persons was 18.9 cases per 100,000 population. Worldwide, 240 million people (2.9% of the population) were living with chronic HBV infection in 2024, of whom 27% had been diagnosed and 4.3% were on treatment, and 0.9 million people were newly infected that year.

Approximately 15%–25% of people with chronic HBV infection develop chronic liver disease, including cirrhosis, liver failure, or liver cancer. Reported annual cirrhosis incidence ranges from 2% to 7% in tertiary care cohorts and was 0.7% in a study of 1506 asymptomatic carriers; persons with cirrhosis progress to decompensated cirrhosis at an estimated 3% annually, with 5-year survival of 84% in compensated and 14%–28% in decompensated cirrhosis. In a cohort followed for a mean of 11.4 years, hepatocellular carcinoma (HCC) incidence ranged from 108 per 100 000 person-years at a baseline HBV DNA level below 300 copies/mL to 1152 per 100 000 person-years at 1 million copies/mL or greater. Among 2,496 patients with non-cirrhotic chronic hepatitis B, incidences of cirrhosis and HCC were 3.99 and 0.43 per 100 person-years. Among 1,644 patients treated with entecavir or tenofovir, the 10- and 15-year cumulative incidences of HCC were 10.9% and 13.2%.

In the United States, 1,769 hepatitis B-related deaths were reported during 2023 (age-adjusted rate 0.44 deaths per 100,000 population). In a cohort of 4389 patients with chronic hepatitis B followed for a mean of 5.38 years, 492 (11%) died, at an average age of 59.8 years, “14 years younger than the general U.S. population”, and hepatitis B was reported on the death certificates of 19% of decedents. Annual U.S. liver-related deaths are projected to increase by 25% from 7900 in 2019 to 9900 in 2030, and annual HCC incidence by 31% from 6500 to 8500 cases. Worldwide, an estimated 1.1 million HBV-related deaths occurred in 2024, an increase of 17% from 2015.

In a meta-analysis of 19 studies comprising 10,311 patients (74% of studies in the Western Pacific Region), predicted mean utility scores were 0.842 for non-cirrhotic chronic HBV infection, 0.820 for compensated cirrhosis, 0.722 for decompensated cirrhosis, and 0.749 for HCC. A meta-analysis of 31 studies estimated the prevalence of depressive symptoms at 19% and of anxiety at 30% among individuals with hepatitis B. In a systematic review of 23 studies of HBV-related stigma, up to 20% of respondents believed they may be denied healthcare and up to 30% that they may experience workplace discrimination.

In U.S. Commercial, Medicare, and Medicaid claims from 2004 to 2015 (33,904 chronic hepatitis B cases), mean annual all-cause healthcare costs among commercially insured patients were $142,870 with decompensated cirrhosis, $124,123 with HCC, and $171,851 with liver transplantation, compared with $18,619 with compensated liver disease (98% non-cirrhotic); patients with compensated liver disease had three times the annual healthcare cost of matched controls without chronic hepatitis B. In the U.S. National Inpatient Sample, total costs of hospitalizations of patients with chronic hepatitis B were $603.82 million in 2016 and $809.01 million in 2019. A U.S. model projected $44,822 million in cumulative direct medical costs associated with HBV between 2020 and 2050.

• B-Well 1 and B-Well 2 were two multicenter, phase 3, randomized, double-blind, placebo-controlled trials with identical designs, conducted in 29 countries. Participants receiving stable nucleos(t)ide analogue (NA) therapy were randomized 2:1 to bepirovirsen or placebo: 981 participants in B-Well 1 and 857 in B-Well 2. Bepirovirsen 300 mg was given subcutaneously twice weekly during weeks 1 and 2 and once weekly during weeks 3 to 24. From week 25 to 48, participants continued NA therapy alone, and those who met prespecified cessation criteria stopped NA therapy at week 48.
• Eligible participants were aged 18 years or older, had chronic HBV infection for 6 months or longer, 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. Participants with a history, suspicion, or evidence of cirrhosis, with HCV, HIV, or HDV coinfection, with eGFR at or below 60 mL/min/1.73 m2, or with a platelet count below 140 x 10⁹/L were excluded. Randomization was stratified by baseline HBsAg (up to 1,000 IU/mL, or above 1,000 and up to 3,000 IU/mL). In each trial, 92% of participants were HBeAg negative.
• The primary endpoint, assessed at week 72, was sustained suppression of HBV DNA below the lower limit of quantification and HBsAg not detected (LOD = 0.05 IU/mL), with or without hepatitis B surface antibodies, 24 weeks after discontinuation of all chronic HBV treatment in the absence of rescue medication, in participants with baseline HBsAg up to 3,000 IU/mL.
• In B-Well 1, the primary endpoint was met by 127 of 650 participants (20%) receiving bepirovirsen and 0 of 328 receiving placebo (common rate difference 17%; 95% CI, 14.6 to 20.3; P<0.0001). In B-Well 2, it was met by 106 of 570 participants (19%) and 0 of 286, respectively (common rate difference 13%; 95% CI, 10.4 to 16.1; P<0.0001). In the pooled trials, 233 of 1,220 bepirovirsen recipients (19%) and 0 of 614 placebo recipients met it.
• In participants with baseline HBsAg up to 1,000 IU/mL (65% of the full analysis set in B-Well 1 and 61% in B-Well 2), the same endpoint was met by 105 of 426 (25%) vs 0 of 214 in B-Well 1 (rate difference 25%; 95% CI, 20.8 to 29.0) and by 95 of 342 (28%) vs 0 of 179 in B-Well 2 (rate difference 28%; 95% CI, 23.3 to 32.8); in the pooled trials, 200 of 768 (26%) vs 0 of 393.
• Sustained HBV DNA suppression below the lower limit of quantification alone, at 24 weeks after cessation of all treatment, was achieved by 151 of 650 (23%) bepirovirsen recipients in B-Well 1 and 132 of 570 (23%) in B-Well 2, and by 0 placebo recipients in either trial.
• The primary endpoint response rate was lower in participants with higher baseline HBsAg, HBeAg-positive status at baseline, or age 65 years or older. In pooled data, response rates were 28% for genotype A, 21% for genotype B, 20% for genotype D, and 15% for genotype C.
• In the pooled trials, 295 of 1,220 bepirovirsen recipients met the criteria to stop NA therapy and stopped it at week 48. At week 72, 233 of these 295 (79%) met the primary endpoint, and 211 of the 233 (91%) maintained response off all HBV treatment at week 96. Through week 96, one of the 84 participants who stopped NA therapy without a sustained response met criteria to restart NA therapy.

• B-Clear was a phase 2b, randomized, investigator-unblinded trial whose intention-to-treat population included 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Participants were randomized 3:3:3:1 to weekly subcutaneous bepirovirsen 300 mg for 24 weeks (group 1), 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then 300 mg for 12 weeks (group 4).
• The B-Clear primary outcome was HBsAg below 0.05 IU per milliliter and HBV DNA below 20 IU per milliliter maintained for 24 weeks after the planned end of bepirovirsen treatment without newly initiated antiviral treatment. It occurred in 6 participants (9%) receiving NA therapy and 7 (10%) not receiving NA therapy in group 1, in 6 (9%) and 4 (6%) in group 2, and in 2 (3%) and 1 (1%) in group 3. In group 1, among participants with baseline HBsAg of 3000 IU or less per milliliter, 5 of 43 (12%) receiving NA therapy and 6 of 24 (25%) not receiving NA therapy had a primary-outcome event.
• B-Sure is an open-label, non-randomized follow-up study in which no further bepirovirsen is administered. Of 11 B-Clear complete responders not receiving NA therapy, 8 (73%) maintained a complete response at month 3 and all 8 maintained functional cure at 21 months; all 6 with month 27 data (33 to 36 months off bepirovirsen) had maintained it. Of 14 B-Clear complete responders receiving NA therapy, 10 (71%) stopped NA therapy 3 months into B-Sure; 8 of these (80%) achieved functional cure 6 months after NA cessation, and all 8 maintained it up to 18 months. Of 26 partial responders receiving NA therapy, 22 (85%) stopped NA therapy, 2 of these (9%) achieved functional cure, and 13 had restarted NA therapy by 24 months after cessation.
• B-Together was a phase IIb, multicentre, randomised, open-label trial in which 108 participants receiving stable NA therapy (Arm 1, n = 55; Arm 2, n = 53) received bepirovirsen 300 mg once weekly for 24 weeks (Arm 1) or 12 weeks (Arm 2), followed by Peg-IFN 180 μg once weekly for up to 24 weeks. The primary outcome, HBsAg and HBV DNA below the lower limit of quantification at every visit for 24 weeks after the planned end of sequential treatment, was achieved by 5 participants (9%) in Arm 1 and 8 (15%) in Arm 2. In HBeAg-negative participants with baseline HBsAg up to 1,000 IU/ml, it was achieved by 3 of 16 (19%) in Arm 1 and 7 of 14 (50%) in Arm 2. All participants who met the primary outcome had baseline HBsAg ≤3,000 IU/ml.

• The label carries a boxed warning for hepatic flares and thrombocytopenia. Bepirovirsen may cause on-treatment hepatic flares with increases in ALT of more than 20 to 40 times the upper limit of normal associated with a decline in HBsAg, some with hyperbilirubinemia; most occurred in the first 12 weeks and resolved when treatment was interrupted or permanently discontinued. It may also cause reductions in platelet counts that may result in “sudden and unpredictable thrombocytopenia, which can be life-threatening”; platelet counts are monitored weekly when 75 x 10⁹/L or greater, and treatment is permanently discontinued if the count falls below 50 x 10⁹/L. Bepirovirsen is contraindicated in patients with acute hepatic impairment, in patients with cirrhosis who have hepatic impairment of Child-Pugh Class A, B, or C, and in patients with a platelet count below 100 x 10⁹/L before treatment.
• The pooled safety population comprised 1,223 participants who received at least one dose of bepirovirsen and 611 who received placebo. In weeks 1 to 36, the most common adverse reactions with bepirovirsen vs placebo were injection site reactions (57% vs 15%), pyrexia (20% vs 4%), fatigue (16% vs 8%), headache (14% vs 12%), and myalgia (8% vs 4%). Of injection site reactions in bepirovirsen recipients, 99% were mild to moderate in severity.
• In a pooled analysis at 72 weeks, adverse events were reported in 91% of bepirovirsen recipients and 73% of placebo recipients, and serious adverse events in 7% and 4%. During the treatment period, adverse events of grade 3 or higher occurred in 16% and 3%, and ALT increases were the most common grade 3 adverse event with bepirovirsen (6%). Adverse events led to discontinuation in 3% of bepirovirsen recipients and <1% of placebo recipients.
• ALT increases of 3 times to 69 times the upper limit of normal were observed, mostly in the first 12 weeks (typically between weeks 5 to 10); 2% of bepirovirsen recipients had ALT increases of 20 times the upper limit of normal or more. During the first 24 weeks, 53 participants (4%) paused treatment for ALT increases, one permanently discontinued for ALT at least 3 times the upper limit of normal with bilirubin at least 2 times the upper limit of normal, and three permanently discontinued for ALT at least 10 times the upper limit of normal for 4 or more weeks.
• In weeks 1 to 36, platelet counts of 100 to less than 140 x 10⁹/L occurred in 37% of bepirovirsen recipients and 7% of placebo recipients. During the first 24 weeks, two bepirovirsen recipients had serious thrombocytopenia with platelet counts <50 × 10⁹/L, one assessed as immune thrombocytopenia, and both recovered with corticosteroid treatment and permanent discontinuation. In total, 8 (<1%) participants met permanent discontinuation criteria and 114 (9%) paused treatment for platelet declines. The mean platelet change from baseline was largest at week 24 (-28.1% from a baseline of 233 x 10⁹/L) and recovered to within 5% of baseline by week 60.
• During the first 24 weeks, 4% of bepirovirsen recipients had an eGFR decrease of more than 30% for 2 or more consecutive readings, and 28 (2%) paused treatment for decreased renal function. Biopsy-confirmed vasculitis occurred in two participants.
• In B-Well 1 and B-Well 2, 43% (517/1,203) of bepirovirsen recipients tested positive for anti-drug antibodies, which were associated with a 26.6% lower systemic clearance of bepirovirsen and did not appear to be associated with a reduced treatment response or differences in the safety profile.

• No U.S. wholesale acquisition cost or average sales price had been published at the time of U.S. approval. A GSK spokesperson stated that the drug’s “list price will become public once pricing and reimbursement discussions have wrapped with payers”. No U.S. budget impact model of bepirovirsen has been published.
• Ionis is eligible for “tiered royalties of 10-12% on net sales of bepirovirsen”.
• Japan, the first country of approval (24 August 2026), scheduled National Health Insurance listing for 14 October 2026 at 183,015 yen per 150 mg (1 mL) prefilled syringe.
• The Japan price was set by the cost accounting method because no listed product had the same indication, pharmacological action, or chemical structure, so no comparator product was identified. The cost components per syringe are 130,733 yen total product cost, 24,164 yen operating profit (15.6% of the price excluding distribution costs), 11,480 yen distribution cost (6.9% of the price excluding consumption tax), and 16,638 yen consumption tax.
• A usefulness premium (I) of 50% and a SENKU premium of 10% were assessed with a premium coefficient of 0, so the price is 183,015 yen before and after premiums. The product qualifies for the innovative new drug price maintenance system and is designated for Japan's cost-effectiveness evaluation (category H1).
• For inpatient DPC payment, the standard drug cost is 366,030 yen per 300 mg administration, with concomitant drug costs in addition; fee-for-service payment until the next medical fee revision was proposed.
• The company's forecast submitted for the Japan listing is 5.6 thousand treated patients and 39.8 billion yen in sales at peak, in year 4.

• No cost-effectiveness analysis of bepirovirsen from a U.S. perspective has been published.
• A U.S. and China threshold analysis of a hypothetical functional cure regimen in a 50-year-old man with HBeAg-negative, noncirrhotic, NUC-suppressed infection estimated that a 30% effective regimen would yield 0.30 QALYs gained per patient in the U.S. and 0.57 in China. With an annual HCC incidence of 0.1% after functional cure, the regimen could be cost-effective at a one-time treatment cost under USD 46,642 in the U.S. and USD 13,008 in China.
• An earlier threshold analysis of a finite 48-week cure regimen estimated that a cure would be cost-saving in the USA at a one-time treatment cost under US$11,944 for patients with cirrhosis and US$6,694 for patients without cirrhosis.
• A lifetime Markov model of bepirovirsen 300 mg weekly for 24 weeks plus background nucleos(t)ide analogues estimated 0.41 to 0.82 incremental QALYs across standard-of-care comparators and a value-based price per dose of $92.92 to $367.44 at a $13,500 per QALY threshold ($426.41 per dose from the societal perspective). Its efficacy parameters came from phase 2 evidence, and B-Well phase 3 results were not incorporated into the base case.
• NICE appraisal ID6608 (single technology appraisal) is in progress, with a committee meeting on 12 January 2027 and expected publication on 10 March 2027. The CDA-AMC reimbursement review (SR0948-000) is active as a complex review filed before a notice of compliance. No ICER review was identified. The 2025 UK horizon-scanning briefing states that the estimated cost “is not yet known”.

• U.S. population estimates: 660,000 persons (0.2% of persons aged 6 years and older) with HBV infection in the National Health and Nutrition Examination Survey (NHANES), of whom 49.8% were aware of their infection; 1.8 million HBV-positive individuals (0.55%) in a 2020 model; and a range of 580,000 to 2.4 million persons cited in the 2023 CDC screening recommendations.
• Diagnosed and treated: the 2020 model estimated approximately 334,800 diagnosed infections (18%) and 90,500 of 534,100 eligible individuals (just under 17%) on treatment. A U.S. projection model (2020 to 2050) used 300,000 diagnosed individuals and 143,500 individuals on antiviral treatment.
• The label population is adults without cirrhosis who “have been on NrtI therapy for at least 6 months and have suppressed HBV deoxyribonucleic acid (DNA)” and have baseline HBsAg of 3,000 IU/mL or less by quantitative testing. GSK states that HBsAg of 1000 IU/mL or less represents “approximately 45% of diagnosed CHB cases globally”. No source reports the share of U.S. adults on NrtI therapy with HBsAg of 3,000 IU/mL or less.
• Dosing: 300 mg, given as two 150 mg prefilled syringes, twice a week in weeks 1 and 2 and once a week in weeks 3 to 24, for a maximum of 24 weeks. Syringes are supplied in cartons of 2 (NDC 0173-0941-39). Early cessation may be considered in patients without HBsAg below 1 IU/mL by week 12, and NrtI therapy continues for at least 24 weeks after the last dose.
• Required testing: quantitative HBsAg before initiation; ALT and total bilirubin weekly through week 12 and every other week from weeks 12 through 24; platelet count weekly through week 24; and eGFR every other week through week 24.
• Published U.S. cost inputs: an annual generic antiviral drug cost of $502 (60% generic tenofovir disoproxil fumarate and 40% generic entecavir; lowest price $325 per year for generic tenofovir disoproxil fumarate); an annual HBV medication cost of $5382 (range $362 to $12,310) from drug sales data in the projection model; and Medicare reimbursement of $59 per HBV DNA test and $10.33 per HBsAg test.

• Indication and eligibility: bepirovirsen is indicated in combination with nucleos(t)ide analog reverse transcriptase inhibitor (NrtI) therapy for adults with chronic HBV infection without cirrhosis who “have been on NrtI therapy for at least 6 months and have suppressed HBV deoxyribonucleic acid (DNA)” and have HBsAg levels of 3,000 IU/mL or less by an FDA-authorized test. The FDA authorized the Roche Elecsys HBsAg II quant II RxDx assay as the companion diagnostic. Treatment lasts up to 24 weeks, and NrtI therapy continues for at least 24 weeks after the last injection. The drug is contraindicated in acute hepatic impairment, in cirrhosis with Child-Pugh Class A, B, or C hepatic impairment, and with a platelet count below 100 x 10⁹/L before treatment.
• Phase 3 efficacy: in B-Well 1 and B-Well 2, two randomized, double-blind, placebo-controlled trials in participants receiving stable NrtI therapy, the primary endpoint (sustained HBV DNA suppression and HBsAg not detected 24 weeks after discontinuation of all chronic HBV treatment, assessed at week 72) was met by 127 of 650 bepirovirsen recipients (20%) and 0 of 328 placebo recipients in B-Well 1 (common rate difference 17%; 95% CI, 14.6 to 20.3; p<0.0001), and by 106 of 570 (19%) and 0 of 286 in B-Well 2 (common rate difference 13%; 95% CI, 10.4 to 16.1; p<0.0001). In participants with baseline HBsAg of 1,000 IU/mL or less, the pooled rate was 26% (200 of 768) vs 0 of 393.
• Durability after NrtI cessation: 295 of 1,220 pooled bepirovirsen recipients met the criteria to stop NrtI therapy and stopped it at week 48. Of these, 233 (79%) met the primary endpoint at week 72, and 211 of the 233 (91%) maintained response off all HBV treatment at week 96. Of the 84 participants who stopped NrtI therapy without a sustained response through week 96, one met protocol criteria to restart NrtI therapy and three others restarted it within one month of cessation without meeting those criteria.
• Boxed warning: bepirovirsen may cause on-treatment hepatic flares with ALT increases of more than 20 to 40 times the upper limit of normal, some with hyperbilirubinemia, most in the first 12 weeks; ALT and total bilirubin are measured before and frequently during treatment. It may also cause “sudden and unpredictable thrombocytopenia, which can be life-threatening”; platelet counts are monitored weekly at 75 x 10⁹/L or greater and more often below that value, and treatment is permanently discontinued if the count falls below 50 x 10⁹/L. Two participants had serious thrombocytopenia below 50 × 10⁹/L, one with immune thrombocytopenia.
• Follow-up and comparator: the primary endpoint was measured 24 weeks after NrtI cessation, and the longest reported follow-up off treatment covers the 295 participants monitored for an additional 48 weeks after stopping NrtI therapy at week 48. Both trials randomized participants to bepirovirsen or placebo added to background NrtI therapy and had no active-comparator group.
• Patient-reported outcomes: neither the label nor the published abstract reports health-related quality of life or patient-reported outcome results.
• Price and budget impact: no U.S. wholesale acquisition cost has been published; GSK stated that the “list price will become public once pricing and reimbursement discussions have wrapped with payers”. No U.S. budget impact model or U.S. cost-effectiveness analysis of bepirovirsen has been published.
• Ongoing studies: B-United (283 participants, bepirovirsen after daplusiran/tomligisiran) and B-Focus (153 participants with HIV-1 and HBV coinfection) are active, not recruiting, with estimated primary completion in May 2027 and April 2027, respectively, and no posted results.