Bepirovirsen FDA Approval: First ASO in HBV Sets a Low Functional Cure Bar With a Narrow Label

FDA Approves First Antisense Oligonucleotide for Chronic Hepatitis B

On October 20, 2026, the U.S. FDA approved Hibsago (bepirovirsen) injection, in combination with existing antiviral therapy, for chronic hepatitis B virus (HBV) infection in certain adults without cirrhosis. This marks the first FDA-approved antisense oligonucleotide for chronic HBV. Hibsago is indicated for adults meeting specific criteria, including suppressed HBV levels and HBsAg levels of 3,000 IU/mL or less. The treatment offers the potential for patients to maintain viral control after discontinuing all HBV therapy. Clinical trials showed that 24% of Hibsago-treated patients met criteria to stop existing medicine, with 19% maintaining viral control and undetectable HBsAg 24 weeks post-treatment cessation. The approval was granted to GSK plc.

• Hibsago (bepirovirsen) represents the first FDA-approved antisense oligonucleotide for chronic hepatitis B, functioning by targeting the virus's genetic instructions to reduce viral load and hepatitis B surface antigen (HBsAg). It is specifically approved for adult patients without cirrhosis who have been on existing antiviral therapy for at least six months, possess suppressed HBV levels, and HBsAg levels of 3,000 IU/mL or less. Patient selection is aided by the Roche Elecsys HBsAg II quant II RxDx assay, a companion diagnostic.
• Clinical trials demonstrated Hibsago's efficacy in enabling patients to achieve sustained viral control even after discontinuing all hepatitis B therapy. Across two studies, 24% of patients receiving Hibsago met the requirements to stop their existing medicine, a significant outcome compared to placebo. Crucially, 19% of these patients maintained viral control and had undetectable HBsAg 24 weeks after stopping all treatment, offering a novel approach to long-term management beyond continuous antiviral medication.
• Hibsago carries a boxed warning for serious liver reactions and low platelet counts, which can increase the risk of potentially life-threatening bleeding. Additional warnings include worsening kidney function and serious inflammatory adverse reactions. Patients require regular blood tests and follow-up to monitor these risks. Despite the safety profile, the FDA granted Hibsago Fast Track, Breakthrough Therapy, and Priority Review designations, highlighting its significance as an advance for a serious disease with unmet needs.

Addressing the Long-Term Burden of Chronic HBV Treatment

Despite effective nucleos(t)ide analogues (NUCs) capable of achieving profound and durable suppression of HBV DNA while improving liver function and histology, robust evidence for long-term clinical outcomes — particularly prevention of hepatocellular carcinoma (HCC) — remains limited. The association between viral suppression and HCC risk reduction is multifactorial, involving the progressive depletion of hepatocytes through covalently closed circular DNA (cccDNA) integration, as well as the prevention of liver fibrosis and cirrhosis. Current indications for therapy require revision and further research to expand treatment to more infected people, given that an estimated 3%–4% of people are living with HBV and face an omnipresent threat of cirrhosis and HCC without intervention.

A fundamental biological obstacle to functional cure is the persistence of the intrahepatic viral reservoir in two distinct forms: episomal cccDNA and genomically integrated HBV DNA (iDNA). Nuclear cccDNA accumulates in hepatocyte nuclei as a stable minichromosome organized by histone and non-histone viral and cellular proteins, and its molecular mechanisms of stability and transcriptional regulation have not been fully elucidated. Critically, even in patients with undetectable intrahepatic cccDNA following long-term NUC therapy, virologic rebound still occurred after NUC cessation — with 12 of 13 patients experiencing HBV DNA rebound to 100 IU/ml within 20 weeks of discontinuation, and the thirteenth rebounding at week 70. This demonstrates that cccDNA elimination alone is insufficient to prevent relapse, implicating integrated HBV DNA as an independent source of viral persistence. Transcriptionally active HBV integration can extend to the entire liver in some HBeAg-negative patients, driving ubiquitous HBsAg expression independent of viral replication and rendering HBsAg an unreliable surrogate marker for viral resolution or functional cure in such patients.

The complexity of intrahepatic HBV burden is further compounded by significant cellular heterogeneity that conventional methods fail to fully capture. RNA-based spatial methods have consistently identified higher intrahepatic viral burden estimates compared with protein-based estimates across all profiled chronic hepatitis B samples, with the discrepancy predominantly driven by HBV iDNA. Two spatially and phenotypically distinct iDNA hepatocyte populations have been identified — including a previously undescribed population exhibiting a periportal zonal preference that is undetectable by protein-based methods — raising new questions about mutational load and HCC risk in regions previously overlooked. On the treatment safety side, long-term use of tenofovir disoproxil fumarate (TDF) has been associated with a significant increase in serum alkaline phosphatase — from a median of 74 U/I to a plateau of 99 U/I after 6 months (P < 0.0001) — alongside renal phosphate losses and decreases in bone mineral density, raising concerns about osteomalacia in at least a subset of patients on prolonged therapy. Taken together, these biological, virological, and safety challenges underscore the substantial unmet need for therapies capable of achieving durable functional cure in chronic hepatitis B.

Hibsago's Pivotal Trial Results: A Path to Treatment Cessation

Recent clinical investigation into chronic HBV infection has yielded meaningful data across several novel and established therapeutic approaches, spanning antisense oligonucleotides, RNA interference, and pegylated interferon-based regimens.

• B-Together (NCT04676724) — Bepirovirsen + Pegylated Interferon-α-2a (Peg-IFN): This Phase 2b, multicentre, randomised, open-label trial enrolled 108 participants on stable nucleos(t)ide analog (NA) therapy, randomised 1:1 to bepirovirsen 300 mg once weekly for 24 weeks (Arm 1) or 12 weeks (Arm 2), followed by Peg-IFN 180 mcg once weekly for up to 24 weeks. The primary outcome — HBsAg <0.05 IU/mL and HBV DNA

• B-Clear (NCT04449029) — Bepirovirsen (GSK3228836): This Phase 2b, multicenter, randomised, partial-blind study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) with chronic HBV infection. Participants were randomised 3:3:3:1 across four treatment arms of bepirovirsen at varying doses and durations (up to 24 weeks), administered as subcutaneous injections with or without loading doses. The primary endpoint was HBsAg below the lower limit of detection and HBV DNA below the lower limit of quantification for 24 weeks after the end of bepirovirsen treatment in the absence of rescue medication.

• VIR-2218 / ALN-HBV Randomised Clinical Trials (NCT02826018 and NCT03672188) — VIR-2218 and ALN-HBV: These studies evaluated two investigational RNA interference therapeutics targeting all major HBV transcripts. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with chronic HBV infection, VIR-2218 was associated with dose-dependent reductions in HBsAg; the greatest mean reduction at Week 20 in participants receiving 200 mg was 1.65 log IU/ml, maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion.

• PEG-B-ACTIVE (NCT01519960) — Peginterferon Alfa-2a: This Phase III study randomised 161 HBeAg-positive immune-active paediatric patients (aged 3 to <18 years) without advanced fibrosis/cirrhosis 2:1 to PegIFN alfa-2a (Group A, n = 101) or no treatment (Group B, n = 50); patients with advanced fibrosis were assigned to PegIFN alfa-2a (Group C, n = 10). HBeAg seroconversion rates at 24 weeks post-treatment were significantly higher in Group A (25.7% vs. 6%; P = 0.0043), as were rates of HBsAg clearance (8.9% vs. 0%; P = 0.03), HBV DNA <2,000 IU/mL (28.7% vs. 2.0%; P < 0.001), undetectable HBV DNA (16.8% vs. 2.0%; P = 0.0069), and ALT normalization (51.5% vs. 12%; P < 0.001). Safety, including incidence of ALT flares and neutropenia, was comparable to the established PegIFN alfa-2a profile in HBV-infected adults or hepatitis C virus-infected children.

Identifying the Right Patients for Hibsago Treatment

Baseline HBsAg level has emerged as the most consistently applied patient selection criterion across bepirovirsen trials, with low baseline HBsAg strongly predicting functional cure outcomes.

• Baseline HBsAg threshold as a primary selection criterion: Phase 2b data from B-Clear established that functional cure responses were concentrated in participants with baseline HBsAg ≤3000 IU/mL. The B-Together study confirmed this finding, with all responders having baseline HBsAg ≤3000 IU/mL. The phase 3 B-Well 1 and B-Well 2 trials enrolled patients with HBsAg levels of more than 100 to 3000 IU per milliliter, formalising this range as the target population.

• Lower HBsAg sub-threshold enrichment strategy: Within the broader ≤3000 IU/mL population, the phase 2b analysis identified that approximately 9–10% of patients with low baseline serum HBsAg (>100 IU/mL and <3000 IU/mL) achieved functional cure after 24 weeks of treatment. A "stop-to-cure" approach in those reaching HBsAg <100 IU/mL has been identified as a strategy warranting further exploration.

• NA therapy status as a stratification variable: B-Clear enrolled both participants receiving stable nucleos(t)ide analogue (NA) therapy (On-NA, n=227) and those not currently receiving NA therapy (Not-on-NA, n=230), allowing independent assessment of bepirovirsen efficacy across these subgroups. The phase 3 B-Well trials restricted enrolment to patients on stable NA therapy, reflecting a refined selection strategy based on phase 2b learnings.

• HBV DNA level as an eligibility criterion: B-Clear required HBV DNA <90 IU/mL for On-NA participants and >2000 IU/mL for Not-on-NA participants, while alanine aminotransferase eligibility thresholds were set at ≤2× upper limit of normal (ULN) for On-NA and <3× ULN for Not-on-NA participants, adding virological and hepatic biomarker gating to patient selection.

• HBeAg-negative, non-cirrhotic status: The optimal dosing regimen entering phase 3 evaluation — 300 mg subcutaneous injection weekly for 24 weeks — was specifically defined for nucleoside analogue-treated HBeAg-negative non-cirrhotic patients with low (<3000 IU/mL) baseline HBsAg, incorporating disease stage and serological marker status as co-selection criteria.

The Emerging Antisense Oligonucleotide Landscape in HBV

Several antisense oligonucleotides (ASOs) targeting HBV RNA transcripts are in clinical development for chronic hepatitis B (CHB), sharing bepirovirsen's mechanism of suppressing viral protein production via post-transcriptional RNA targeting. Alongside bepirovirsen (GSK3228836), the agents GSK3389404, ALG-020572 (Aligos), RO7062931 (Roche), and AHB-137 have been evaluated in clinical trials for CHB, with varying degrees of HBsAg suppression reported across studies.

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Hibsago's Approval: A New Era for Chronic HBV Functional Cure

The recent FDA approval of Hibsago (bepirovirsen) marks a significant stride forward in the long-standing battle against chronic hepatitis B virus (HBV) infection. As the first approved antisense oligonucleotide (ASO) for this condition, Hibsago introduces a novel mechanism of action, directly targeting HBV messenger RNAs to suppress viral protein production. This approach offers a tangible path toward a functional cure, a highly sought-after outcome where patients can achieve sustained viral control and undetectable hepatitis B surface antigen (HBsAg) even after discontinuing all antiviral therapy. This is a profound shift from the current standard of care, which often involves lifelong nucleos(t)ide analog therapy with limited rates of HBsAg seroclearance.

The approval is specifically for adults without cirrhosis who meet certain criteria, including suppressed HBV levels and HBsAg levels of 3,000 IU/mL or less. This patient stratification is critical, as existing evidence suggests that individuals with lower baseline HBsAg are more likely to achieve a functional cure. While the clinical trials demonstrated that 19% of treated patients maintained viral control 24 weeks post-treatment cessation, this also highlights that a substantial proportion may not achieve this durable response or could experience relapse. Studies exploring sequential therapy with pegylated interferon-α-2a after bepirovirsen have shown promise in potentially reducing these relapse rates, suggesting that combination strategies will be key to maximizing patient benefit.

However, the journey with novel therapeutics always involves careful consideration of risks. Transient, self-resolving alanine aminotransferase (ALT) flares were observed in clinical trials, sometimes correlating with HBsAg decline. While generally mild, these events necessitate vigilant monitoring. The broader landscape of ASO development for HBV also points to the complexity of these agents, with some investigational compounds encountering challenges in identifying efficacious dosing regimens or demonstrating a narrow therapeutic window. For Hibsago, this underscores the importance of precise patient selection and ongoing research to optimize treatment protocols and further enhance long-term outcomes. This approval firmly establishes ASOs as a cornerstone of future HBV treatment, paving the way for continued innovation in this critical therapeutic area.