---
title: "Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Efficacy and safety"
description: "Formulary evidence on Hibsago (bepirovirsen, GSK3228836) in Chronic hepatitis B virus infection in adults without cirrhosis: Efficacy and safety. Topics: Summary: phase 3 efficacy (B-Well 1 and B-Well 2); Summary: phase 2 evidence (B-Clear, B-Sure, and B-Together); Summary: safety (B-Well 1 and B-Well 2). 3 evidence topics quoted from 9 sources."
canonical: "https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/executive-summary/efficacy-and-safety"
published: "2026-10-21T22:39:04-04:00"
modified: "2026-10-22T19:07:03-04:00"
---

# Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Efficacy and safety

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## 1.1.2 Bepirovirsen Efficacy and Safety

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### Summary: phase 3 efficacy (B-Well 1 and B-Well 2)

- 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.

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF); [GSK press release, B-Well results (2026)](https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/)

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### Summary: phase 2 evidence (B-Clear, B-Sure, and B-Together)

- 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.

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027); [ClinicalTrials.gov NCT04954859](https://clinicaltrials.gov/study/NCT04954859); [Lim et al. (2025a)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20UP%20to%202%20years%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20Not-on-NA%20responders%20-%20B%20Sure%20third%20report.pdf); [Lim et al. (2025b)](https://ionis.com/sites/default/files/2026-06/Lim%20et%20al%20-%20Up%20to%2018%20months%20functional%20cure%20in%20response%20to%20bepirovirsen%20therapy%20in%20B-Clear%20on%20NA%20responders%20-%20B-Sure%20third%20report.pdf); [Buti et al. (2025)](https://doi.org/10.1016/j.jhep.2024.08.010)

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### Summary: safety (B-Well 1 and B-Well 2)

- 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.

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF); [Hou et al. (2026a)](https://pubmed.ncbi.nlm.nih.gov/42206582/); [Fierce Pharma (2026)](https://www.fiercepharma.com/pharma/gsk-brings-promise-functional-cure-hepatitis-b-finish-line-fda-nod-hibsago)

## Related pages
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