Gastroenterology · Medical Literature
[News] EASL Congress 2026
Abstract
24 weeks of treatment with the antisense oligonucleotide bepirovirsen, which targets all hepatitis B virus (HBV) transcripts, resulted in significantly more patients with chronic HBV infection achieving functional cure (defined as an HBV DNA level below the lower limit of quantification, undetectable HBsAg, and no receipt of rescue therapy) by week 72 than did treatment with placebo, according to data from the B-Well trials, presented by Seng-Gee Lim (Singapore). In the two trials, adults with non-cirrhotic chronic HBV receiving stable nucleoside or nucleotide analogue (NA) therapy and an HBsAg level of 100–3000 IU/mL were randomly assigned (2:1) to receive 24 weeks of bepirovirsen or placebo; eligible patients could discontinue NAs at week 48.
Clinical relevance
In non-cirrhotic adults with virologically suppressed chronic HBV infection on stable nucleoside/nucleotide analogue (NA) therapy, does a 24-week course of the antisense oligonucleotide bepirovirsen (300 mg subcutaneously weekly) achieve a significantly higher rate of functional cure at week 72 compared with placebo? __SNAPSHOT__ {"studyDesign":"Two replicate, randomized, double-blind, placebo-controlled, multinational Phase 3 trials (B-Well 1 [NCT05630807] and B-Well 2 [NCT05630820]); conducted in parallel with simultaneous pre-specified pooled analyses. Data presented at EASL Congress 2026 (Barcelona, May 27–30) and concurrently published in the New England Journal of Medicine (May 28, 2026; DOI: 10.1056/NEJMoa2515131).","setting":"29 countries across Europe, Asia-Pacific, and the Americas; multinational academic and clinical hepatology centres. Recruitment: December 2022 – May 2025.","sampleSize":"n = 1,838 total (B-Well 1: bepirovirsen n = 650, placebo n = 328; B-Well 2: bepirovirsen n = 570, placebo n = 286); pooled bepirovirsen n = 1,220–1,224, pooled placebo n = 611–614 (minor variation due to analysis set definitions). Randomisation ratio 2:1 (bepirovirsen:placebo).","population":"Non-cirrhotic adults with chronic HBV infection who had been receiving stable NA therapy for ≥6 months; baseline HBsAg 100–3,000 IU/mL; HBV DNA 90% of participants.","intervention":"Subcutaneous bepirovirsen 300 mg once weekly for 24 weeks (with loading doses on days 4 and 11), added to background NA therapy. NA therapy continued through week 48; participants meeting pre-defined virologic criteria (HBV DNA < LLOQ and undetectable HBsAg from week 24 to week 46) were eligible to discontinue all HBV therapy at week 48.","comparator":"Matched placebo subcutaneous injection once weekly for 24 weeks, with background NA therapy on the same schedule as the intervention arm.","primaryOutcome":"Functional cure (FC) at week 72, defined as HBV DNA below the LLOQ (< 20 IU/mL or target not detected) AND HBsAg not detected by qualitative assay (< 0.05 IU/mL) AND no receipt of rescue therapy — representing sustained off-treatment virologic and serologic control 24 weeks after NA discontinuation.","followUp":"72 weeks from randomisation (24 weeks of treatment + 24 weeks of continued NA ± discontinuation criteria assessment + 24 weeks off all therapy for those eligible). Durability follow-up to week 96 is planned and ongoing.","fundingSource":"Industry (GSK; co-developed with Ionis Pharmaceuticals). Seven authors disclosed employment by GSK; six held GSK stock or stock options. Multiple investigator authors disclosed consultancy fees, grants, or research funding from various industry sponsors."}
Key findings
PRIMARY OUTCOME: The rate of functional cure at week 72 was significantly higher with bepirovirsen than placebo in both trials. In B-Well 1: 127/650 (20%) vs. 0/328 (0%), common risk difference +17.5 percentage points (P < 0.001). In B-Well 2: 106/570 (19%) vs. 0/286 (0%), common risk difference +13.3 percentage points (P < 0.001). In the pooled analysis, 233/1,220 (19%) bepirovirsen-treated patients vs. 0/614 (0%) placebo patients achieved FC (P < 0.001 in both trials). No confidence intervals for the primary outcome were reported in the available sources. NNT for functional cure (overall population, calculated from pooled data): approximately 5.3 (calculated). KEY SECONDARY OUTCOME: In the pre-specified subgroup with baseline HBsAg ≤ 1,000 IU/mL (representing ~45% of enrolled participants), FC rates were 25% in B-Well 1 and 28% in B-Well 2 (both P < 0.001 vs. placebo); pooled rate 26% (200/768 vs. 0/393). NNT in this subgroup: approximately 3.8 (calculated). ADDITIONAL SECONDARY OUTCOME: Sustained HBV DNA < LLOQ at week 72 after stopping all treatment was achieved in 23% of all bepirovirsen-treated patients (283/1,220 vs. 0/614; P < 0.001) and 31% of those with baseline HBsAg ≤ 1,000 IU/mL (237/768 vs. 0/393; P < 0.001). NA DISCONTINUATION: 24% of bepirovirsen recipients in both trials met the criteria for stopping NA therapy at week 48, vs. 0% of placebo recipients. EXPLORATORY ANALYSIS: At 1 year after end of treatment, 49% of bepirovirsen recipients achieved qHBsAg ≤ 100 IU/mL. SAFETY: In pooled analysis, adverse events (AEs) were reported in 91% of bepirovirsen recipients vs. 73% of placebo recipients; serious AEs in 7% vs. 4%, respectively. Grade ≥ 3 AEs occurred in 16% (bepirovirsen) vs. 3% (placebo). The most common grade ≥ 3 AE was ALT elevation (6% bepirovirsen). Most frequent AEs overall were injection-site erythema (31% vs. 2%), injection-site pain (23% vs. 5%), and transient ALT elevation. Treatment discontinuation due to AEs occurred in 3% of the bepirovirsen group. No new major safety signals were identified beyond prior phase 2b experience.
Practice implications
WHAT WAS ESTABLISHED: Two replicate phase 3 RCTs, totaling 1,838 participants, consistently demonstrated that a finite 24-week course of bepirovirsen achieves functional cure in approximately 19–20% of carefully selected non-cirrhotic patients with virologically suppressed chronic HBV on NA therapy — compared with 0% on placebo. This represents a clinically important and statistically unambiguous effect in a disease where functional cure rates with current standard-of-care NA therapy are estimated at 3,000 IU/mL, HBeAg-positive disease with high viral loads, or those intolerant/naïve to NA therapy was not evaluated. (4) Long-term safety data are limited to 72 weeks. (5) The grade ≥ 3 ALT flare rate (6%) warrants caution, particularly if studied in patients with compensated cirrhosis, who may be at risk of decompensation. APPLICABILITY: Findings apply most directly to the enrolled phenotype: non-cirrhotic, NA-suppressed, HBeAg-negative-predominant adults with baseline HBsAg 100–3,000 IU/mL. Approximately two-thirds of enrolled patients were Asian, which may limit generalisability to other racial/ethnic groups. PRACTICE IMPLICATIONS: These results are likely to be practice-changing for the eligible population upon regulatory approval, though formal guideline updates and regulatory decisions (anticipated Q3 2026) are still pending at the time of this report. Clinicians should note that only a subset of the global CHB population will qualify, and broader implementation will require systematic quantitative HBsAg testing. NOTE: This summary is based on congress presentation data and concurrent NEJM publication. Full supplementary data, pre-specified statistical analysis plans, and confidence intervals for all endpoints should be reviewed in the primary publication. __LIMITATIONS__ 1. INDUSTRY SPONSORSHIP: Funded entirely by GSK, with seven author-employees and six holding company equity — introduces risk of reporting and framing bias, though the replicate trial design, large sample, and independent data safety monitoring committee partially mitigate this. 2. FUNCTIONAL CURE AS SURROGATE: FC (HBsAg loss + HBV DNA suppression) is a validated but still intermediate endpoint; reduction in hard outcomes (HCC incidence, liver-related mortality, cirrhosis progression) was not assessed in these trials. 3. DURABILITY UNKNOWN: The primary endpoint was week 72 (24 weeks off therapy); longer-term relapse rates are not yet reported. Week 96 follow-up data are pending. 4. NARROW ELIGIBLE POPULATION: Exclusion of patients with cirrhosis, HIV, HDV, HCV coinfection, HBsAg > 3,000 IU/mL, HBeAg-positive patients with high viral load, and those on interferon within 12 months substantially limits generalisability and leaves the majority of the global CHB population unrepresented. 5. MAJORITY NON-RESPONDERS: 80% of treated patients did not achieve functional cure; the drug is not yet optimised as monotherapy for most CHB patients. 6. SAFETY SIGNAL: Grade ≥ 3 ALT elevations in 6% and a fivefold higher rate of grade ≥ 3 AEs overall (16% vs. 3%) require close monitoring protocols if used in clinical practice. ALT flares may carry decompensation risk in patients with cirrhosis (not studied). 7. SUBGROUP ANALYSIS LIMITATIONS: Relatively small numbers in racial/ethnic and geographic subgroups may limit subgroup-level generalisability; central stratification during randomisation may have introduced baseline HBsAg level imbalances across country strata. 8. UNBLINDING RISK: High rates of injection-site reactions (erythema 31% vs. 2%) in the bepirovirsen group may have partially unblinded participants and site staff. 9. STATISTICAL VS. CLINICAL SIGNIFICANCE: While both are compelling here, the lack of reported confidence intervals in abstract/congress data prevents full evaluation of precision of effect estimates. 10. NO ACTIVE COMPARATOR: No comparison to pegylated interferon or emerging HBsAg-lowering agents (e.g., siRNA therapies); adds uncertainty about relative positioning in an evolving treatment landscape. __BOTTOM_LINE_CATEGORY__ practice_changing __BOTTOM_LINE__ In two replicate phase 3 RCTs enrolling 1,838 non-cirrhotic adults with virologically suppressed chronic HBV on NA therapy, a finite 24-week course of bepirovirsen 300 mg subcutaneously weekly achieved functional cure in approximately 19–20% of patients overall (vs. 0% placebo; P < 0.001 in both trials) and 25–28% of those with baseline HBsAg ≤ 1,000 IU/mL — representing a transformative advance over current NA therapy, which achieves functional cure in < 1% of patients annually. Clinicians should recognise that eligibility is restricted to a specific, carefully defined non-cirrhotic, NA-suppressed phenotype, that long-term durability and hard outcome data beyond week 72 are not yet available, and that grade ≥ 3 ALT flares (6%) require prospective monitoring protocols. Pending regulatory approval (FDA decision anticipated Q3 2026), practice-level adoption should await formal guideline integration, and implementation will require systematic quantitative HBsAg testing to identify candidates most likely to respond.