Bepirovirsen (IONIS-HBVRx/GSK3228836): An Investigational Antisense Oligonucleotide Therapy for Chronic Hepatitis B

Executive Summary

Bepirovirsen (also known as IONIS-HBVRx and GSK3228836) is an investigational antisense oligonucleotide (ASO) therapy representing a potentially transformative approach for the treatment of chronic hepatitis B (CHB). Developed by Ionis Pharmaceuticals and licensed to GSK for late-stage development, bepirovirsen is distinguished by a unique triple-action mechanism that combines direct antiviral activity with immune stimulation. It is designed to degrade all hepatitis B virus (HBV) RNA transcripts, thereby suppressing viral replication and the production of viral proteins, most notably the hepatitis B surface antigen (HBsAg), which is central to the virus's ability to evade the host immune system. Concurrently, bepirovirsen functions as an agonist of Toll-like receptor 8 (TLR8), stimulating innate immune responses. This dual-pronged attack on the virus—reducing its immunosuppressive shield while simultaneously boosting the host's immune response—positions bepirovirsen as a leading candidate in the global pursuit of a "functional cure" for CHB.

The clinical development program for bepirovirsen is extensive and strategically designed to demonstrate its efficacy, safety, and potential role in future treatment paradigms. The landmark Phase 2b B-Clear trial, published in the New England Journal of Medicine, established proof-of-concept, demonstrating that 24 weeks of treatment resulted in a sustained functional cure in 9-10% of participants. Critically, the trial identified a sub-population of patients with low baseline HBsAg (≤3000 IU/mL) who achieved significantly higher response rates, a finding that has been instrumental in de-risking the program and shaping the design of the ongoing, fully enrolled pivotal Phase 3 B-Well trials. Further Phase 2 studies, such as B-Together, have provided evidence that sequential therapy with an immunomodulator like pegylated interferon can enhance the durability of response, supporting bepirovirsen's potential as a backbone therapy. The comprehensive program also includes mechanistic studies (B-Fine) to confirm intrahepatic activity and long-term follow-up studies (B-Sure) to establish durability.

Recognized for its potential to address a significant unmet medical need, bepirovirsen has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) and SENKU designation in Japan. As the only single agent in Phase 3 development to have demonstrated the potential for clinically meaningful functional cure rates, bepirovirsen is poised to potentially redefine the treatment landscape for CHB, shifting the goal from lifelong viral suppression to a finite, curative therapy. Key data from the pivotal B-Well program are anticipated in late 2025, representing a major inflection point for the asset, its developers, and the millions of patients living with CHB worldwide.

Introduction: The Quest for a Functional Cure in Chronic Hepatitis B (CHB)

The Global Burden and Pathophysiology of CHB

Chronic hepatitis B (CHB) represents a formidable global health challenge, with an estimated 257 to 300 million people living with the infection worldwide.[1] The disease is a leading cause of significant morbidity and mortality, contributing to nearly one million deaths annually from complications such as liver cirrhosis and hepatocellular carcinoma (HCC).[1] The pathophysiology of CHB is characterized by the remarkable persistence of the hepatitis B virus (HBV). A key element of this persistence is the formation of a stable viral reservoir in the nucleus of infected liver cells (hepatocytes) in the form of covalently closed circular DNA (cccDNA).[6] This cccDNA molecule serves as a persistent template for the transcription of all viral RNAs, including pregenomic RNA (pgRNA) required for viral replication and messenger RNAs (mRNAs) that are translated into viral proteins.[6]

Among these viral proteins, the hepatitis B surface antigen (HBsAg) plays a central role in the chronicity of the infection. Produced in vast excess, HBsAg is believed to induce a state of T-cell exhaustion, effectively crippling the host's adaptive immune response and preventing viral clearance.[9] This immune tolerance allows the virus to replicate unchecked for years, leading to chronic inflammation and progressive liver damage.

Limitations of Current Standard-of-Care and the Unmet Medical Need

The current standard-of-care for CHB primarily involves the use of nucleos(t)ide analogues (NAs), such as tenofovir and entecavir. These agents are highly effective at inhibiting the viral polymerase, thereby suppressing HBV DNA replication to undetectable levels.[13] While NA therapy significantly reduces the risk of liver disease progression and HCC, it has a major limitation: it has a minimal effect on HBsAg levels and does not eliminate the cccDNA reservoir.[9] Consequently, cessation of NA therapy almost invariably leads to viral rebound, necessitating lifelong treatment for the vast majority of patients.[4] This reality imposes a significant treatment burden, including the costs of long-term medication, the need for continuous monitoring, and the psychological impact of living with a chronic infectious disease.[4]

Defining the Therapeutic Goal: Functional Cure

Given the limitations of existing therapies, the primary goal of novel drug development in CHB has shifted from mere viral suppression to achieving a "functional cure".[1] A functional cure is defined as the sustained loss of HBsAg and undetectable levels of HBV DNA in the serum for at least 6 to 12 months after the completion of a finite course of therapy.[3] This state signifies that the host's immune system has successfully regained control over the virus, eliminating the need for ongoing treatment and substantially reducing the long-term risks of cirrhosis and HCC.[4] The pursuit of a functional cure represents a paradigm shift in CHB management and is the central objective driving the development of bepirovirsen and other next-generation therapies.

Bepirovirsen: A Profile of an Investigational Antisense Oligonucleotide

Drug Identity, Synonyms, and Development History

Bepirovirsen is an investigational biotech therapeutic classified as an antisense oligonucleotide (ASO). It is identified by the DrugBank accession number DB16202 and has been assigned multiple synonyms and development codes throughout its history, including IONIS-HBVRx, GSK3228836, ISIS 505358, ISIS-GSK3Rx, and GSK'836.[1]

The drug was discovered and initially developed by Ionis Pharmaceuticals, a company at the forefront of RNA-targeted therapeutics.[1] Following promising results from Phase 2 studies, GSK exercised its option to license bepirovirsen in August 2019. Under the terms of the agreement, Ionis received a $25 million license fee and is eligible for up to $262 million in milestone payments, in addition to tiered royalties on net sales.[29] GSK is now responsible for all subsequent development, regulatory, and commercialization activities, leveraging its extensive expertise in infectious diseases to advance the program.[13]

Chemical Properties and Formulation

Bepirovirsen is chemically described as a 20-mer 2′-O-methoxyethyl (2′-MOE) modified ASO, with the CAS Number 1403787-62-1.[8] It is a white to off-white solid powder with a molecular weight of 7344.00 and is soluble in water.[30] The drug is designed for subcutaneous administration. While initial clinical trials used a vial formulation, a ready-to-use prefilled syringe (PFS) assembled with a safety syringe device (SSD) has since been developed to enhance convenience and facilitate patient self-administration.[36] A Phase 1 trial (NCT06058390) confirmed the safety, tolerability, and relative bioavailability of the PFS SSD formulation compared to the vial.[36]

Mechanism of Action: A Triple-Action Attack on HBV

Bepirovirsen employs a multifaceted mechanism of action that attacks CHB on two distinct fronts, a strategy GSK refers to as a "triple action" approach.[1]

1. RNA Degradation (Antisense Mechanism): As an ASO, bepirovirsen is a short, synthetic, single-stranded nucleic acid designed to be complementary to a specific RNA sequence. It targets a highly conserved region present in all HBV RNA transcripts, including pgRNA and all viral mRNAs.[8] Upon binding to its target RNA within an infected hepatocyte, bepirovirsen forms an RNA-DNA duplex. This duplex is recognized by a ubiquitous cellular enzyme, RNase H, which then cleaves and degrades the viral RNA strand.[3] This process effectively silences viral gene expression, leading to a profound reduction in the production of all viral proteins, including HBsAg, and a halt in viral replication, measured by a decrease in HBV DNA.[1]
2. Immune Stimulation (TLR8 Agonism): In addition to its primary antisense activity, bepirovirsen possesses an intrinsic ability to stimulate the innate immune system by acting as an agonist for Toll-like receptor 8 (TLR8).[3] TLR8 is an immune receptor that recognizes single-stranded RNA, such as that from viral pathogens. Activation of TLR8 triggers downstream signaling cascades that lead to the production of pro-inflammatory cytokines and chemokines, helping to mount a robust antiviral immune response.[1]

The strategic advantage of this dual-mechanism approach cannot be overstated. The central challenge in curing CHB is overcoming the profound immune exhaustion induced by the high viral antigen load, particularly HBsAg. Bepirovirsen tackles this problem directly. Its ASO activity acts as a "knockdown" agent, reducing the HBsAg burden that suppresses the immune system. Simultaneously, its TLR8 agonist activity provides a "boost," directly stimulating the now-unburdened immune system to recognize and attack the remaining infected cells. This integrated approach—simultaneously removing the "brakes" and pressing the "accelerator" on the immune system—is hypothesized to be more effective at achieving a durable, off-treatment functional cure than therapies that address only one of these pathways. This unique mechanism underpins GSK's strategy to develop bepirovirsen not only as a monotherapy but also as a potential cornerstone or "backbone" for future combination and sequential treatment regimens.[1]

The Bepirovirsen Clinical Development Program: A Comprehensive Analysis

The clinical development of bepirovirsen has been methodical and comprehensive, progressing from early-phase safety and mechanistic studies to large-scale pivotal trials designed to confirm its efficacy and support global regulatory submissions.

A. Early-Phase and Mechanistic Insights

Phase 1/2a Studies (NCT02981602)

The initial clinical evaluation of bepirovirsen was conducted in a Phase 2, double-blind, randomized, placebo-controlled study (NCT02981602) involving both treatment-naïve and NA-treated patients with CHB.[39] This first-in-human study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary antiviral activity of the drug. The results demonstrated a favorable safety profile and provided the first clinical evidence of target engagement, with dose-dependent reductions in serum HBsAg concentrations observed in patients receiving 300 mg of bepirovirsen.[9] These encouraging early data supported the drug's advancement into more extensive Phase 2b trials.[9]

The B-Fine Study (NCT04544956)

To gain a deeper understanding of the drug's mechanism, GSK initiated the B-Fine study (NCT04544956), an open-label, Phase 2a multi-center trial specifically designed to explore the therapeutic mechanism of bepirovirsen in HBeAg-negative CHB patients on stable NA therapy.[24] A key feature of this study is the use of repeat fine needle aspirations (FNA) of the liver to investigate the intrahepatic virologic and immunologic effects of the treatment.[44]

The B-Fine study is critical because it moves beyond measuring peripheral blood markers to directly assessing the drug's activity at the site of infection. While serum levels of HBsAg and HBV DNA are essential regulatory endpoints, understanding the corresponding changes within the liver provides definitive mechanistic proof. Through FNA, investigators can correlate reductions in serum HBsAg with the degradation of intrahepatic HBV RNA, confirming the drug's primary antisense mechanism. Furthermore, these liver samples allow for the characterization of changes in the local immune microenvironment, providing direct evidence of the drug's immunomodulatory effects via TLR8 agonism. This level of mechanistic detail is invaluable for building a robust data package for regulatory authorities and for identifying potential biomarkers that could predict patient response, thereby strengthening the entire development program.

B. Mid-Stage Efficacy and Safety Evaluation

The B-Clear Trial (Phase 2b, NCT04449029): Analysis of Landmark NEJM Data

The B-Clear trial was a large, randomized, Phase 2b study that served as the primary proof-of-concept for bepirovirsen's efficacy. The study, whose results were prominently published in the New England Journal of Medicine, enrolled 457 participants with CHB, comprising two parallel cohorts: one on stable NA therapy (n=227) and one not on NA therapy (n=230).[3] Within each cohort, participants were randomized to one of four treatment arms for 12 or 24 weeks.[3]

The primary composite endpoint was the proportion of patients achieving sustained virologic response (SVR), defined as HBsAg levels below the lower limit of detection and HBV DNA levels below the lower limit of quantification, maintained for 24 weeks after the end of treatment without the need for rescue medication.[8]

The results showed that in the most effective arm (300 mg weekly for 24 weeks), 9% of patients on NA therapy and 10% of patients not on NA therapy achieved the primary endpoint.[3] The safety profile was deemed acceptable, with the most common adverse events being injection-site reactions, pyrexia, and transient, self-resolving elevations in alanine aminotransferase (ALT), which were often considered indicative of a desired immune response. No new safety signals were identified that would preclude further development.[3]

The most significant outcome of the B-Clear trial was the identification of a key predictor of response. Analysis revealed that patients with low baseline HBsAg levels (≤3000 IU/mL) had a substantially higher probability of achieving a functional cure, with response rates reaching 16% to 25% in this subgroup.[2] This finding was pivotal, as it transformed the perception of bepirovirsen from a drug with modest overall efficacy to one with significant potential in a clearly defined patient population. This insight directly de-risked the program and provided a clear, data-driven strategy for the pivotal Phase 3 trials, which were subsequently designed to enrich for this more responsive patient group.[1]

The B-Together Trial (Phase 2b, NCT04676724): Investigating Sequential Therapy with Peg-IFN

Building on the B-Clear results, the B-Together trial was designed to explore whether a sequential therapy approach could improve outcomes. This Phase 2b, open-label study randomized 108 patients on stable NA therapy to receive bepirovirsen for either 12 or 24 weeks, followed by up to 24 weeks of treatment with pegylated interferon (Peg-IFN), a known immunomodulator.[53]

The primary endpoint was achieved by 9% of patients in the 24-week bepirovirsen arm and 15% in the 12-week bepirovirsen arm.[53] A crucial finding emerged from an indirect comparison with the B-Clear data: the addition of Peg-IFN did not appear to convert bepirovirsen non-responders into responders. Instead, its primary benefit was in preventing post-treatment relapse among those who had already responded to bepirovirsen.[56] This provided the first clinical proof-of-concept for a "knockdown-then-boost" strategy, where an initial reduction in HBsAg load by bepirovirsen creates a more favorable environment for a subsequent immunomodulatory agent to consolidate the response and enhance its durability. This result validates GSK's broader strategic interest in exploring bepirovirsen as a backbone for sequential regimens with various immunomodulators.[1]

C. The Pivotal Phase 3 Program: The B-Well Trials (NCT05630807, NCT05630820)

Based on the strength of the Phase 2b data, GSK advanced bepirovirsen into a large-scale Phase 3 program in early 2023, consisting of two global, randomized, double-blind, placebo-controlled trials: B-Well 1 (NCT05630807) and B-Well 2 (NCT05630820).[1] These trials are designed to confirm the efficacy and safety of bepirovirsen in NA-treated patients with CHB.

Reflecting the key learning from the B-Clear study, the B-Well trials are specifically designed to enroll patients with baseline HBsAg levels of >100 IU/mL and ≤3000 IU/mL, the population most likely to respond.[11] The study design is multi-stage: participants first receive 24 weeks of double-blind treatment with either bepirovirsen or placebo while continuing their NA therapy. This is followed by a 24-week period on NA therapy alone. At Week 48, participants who meet specific criteria for response will be eligible to stop their NA therapy and will be followed for an additional 48 weeks to assess the durability of the functional cure.[52]

Both trials are fully enrolled, with B-Well 1 having 981 participants and B-Well 2 having 871 participants, and are currently active but not recruiting.[11] The estimated primary completion date for these pivotal studies is November 2025, which represents the most significant near-term catalyst for the bepirovirsen program.[11]

D. Assessing Durability: The B-Sure Long-Term Follow-Up Study (NCT04954859)

To address the critical question of long-term durability, GSK initiated the B-Sure study (NCT04954859), a prospective, multi-center, long-term follow-up study.[1] This study enrolls participants who achieved a complete or partial response in the parent bepirovirsen trials (including B-Clear and B-Together) and follows them for up to an additional 33-36 months.[1]

Establishing the long-term durability of HBsAg and HBV DNA loss is essential for demonstrating the value of a finite treatment over lifelong NA therapy. By proactively collecting this data in a dedicated study, GSK is building a robust evidence base to support regulatory submissions and, ultimately, to convince clinicians and payers of the drug's long-term benefit. Preliminary data presented from B-Sure have been encouraging, showing that a high proportion of responders from B-Clear maintained their response after entering the long-term follow-up, including those who were able to cease NA therapy.[51]

Strategic Evolution: Bepirovirsen as a Backbone Therapy

GSK's development strategy for bepirovirsen extends beyond its use as a monotherapy. The company is actively exploring its potential as a foundational "backbone" agent for various sequential and combination regimens, aiming to increase functional cure rates across a broader patient population.

Combination with siRNA: The B-UNITED Trial (NCT06537414)

The B-UNITED study is a Phase 2b trial investigating a novel sequential regimen of an siRNA therapeutic (daplusiran/tomligisiran) followed by bepirovirsen in patients on NA therapy.[71] This trial represents a sophisticated evolution of the "knockdown-then-boost" strategy. The rationale is that an initial, deep knockdown of HBsAg by a potent siRNA could create an even more favorable immune environment for bepirovirsen's subsequent immunomodulatory (TLR8 agonist) effect to drive a durable cure. Pharmacokinetic and pharmacodynamic modeling simulations have predicted an added benefit from this sequential approach.[37] Success in this trial could establish a new best-in-class treatment paradigm and solidify bepirovirsen's role as an essential immunomodulatory component in future CHB cure regimens.

Expansion into Special Populations: The B-Focus Trial (NCT06497504)

Recognizing the high unmet need in co-infected populations, GSK has initiated the B-Focus trial (NCT06497504), a Phase 2 study evaluating the efficacy and safety of bepirovirsen in participants with HIV/HBV co-infection who are on stable antiretroviral therapy.[23] This expands the potential patient population for bepirovirsen and addresses a group often excluded from clinical trials.

Lessons from Discontinued Approaches (GSK3528869A)

GSK's strategic focus on bepirovirsen was further clarified by its decision in early 2025 to discontinue the development of GSK3528869A, a therapeutic vaccine candidate for CHB.[59] After a Phase 1/2 study failed to meet its efficacy endpoint, the company prioritized its resources on the more promising bepirovirsen program. This decision underscores the significant challenges in developing effective immunotherapies for CHB and highlights GSK's data-driven approach to pipeline management.

Regulatory and Strategic Outlook

Implications of FDA Fast Track and Japanese SENKU Designations

Bepirovirsen's development has been formally recognized by key global regulatory agencies. In February 2024, the U.S. FDA granted the drug Fast Track designation, a status intended to facilitate development and expedite the review of therapies for serious conditions with unmet medical needs.[2] Later in 2024, Japan's Ministry of Health, Labour and Welfare (MHLW) granted SENKU (SAKIGAKE) designation, which serves a similar purpose of expediting review in Japan.[1] These designations are based on the promising data from the Phase 2b program and acknowledge the potential for bepirovirsen to provide a significant advance in the treatment of CHB. They allow for more frequent interactions with regulators and may lead to eligibility for accelerated approval and priority review pathways.

Competitive Landscape: Positioning Against Other Modalities

The landscape of novel CHB therapies is dynamic, with multiple companies pursuing a functional cure through various mechanisms. Bepirovirsen's main competitors fall into two categories:

• Other RNA-Targeting Therapies: This includes small interfering RNA (siRNA) candidates, such as Vir Biotechnology's elebsiran (VIR-2218) and Arbutus Biopharma's imdusiran (AB-729).[76] These agents also work by knocking down HBV RNA but lack the intrinsic immunomodulatory activity of bepirovirsen. As a result, they are primarily being developed as part of combination regimens, often with immunomodulators like interferon. Bepirovirsen's ability to act as both a knockdown agent and an immune stimulant in a single molecule could be a significant competitive advantage.
• Gene Editing Therapies: A newer class of therapies aims to directly edit or eliminate the cccDNA reservoir in hepatocytes. Companies like Precision BioSciences are advancing candidates such as PBGENE-HBV, which uses the ARCUS gene editing platform, into early-stage clinical trials.[7] While potentially offering a true sterilizing cure, these technologies are at a much earlier stage of development and face higher hurdles regarding long-term safety and delivery. Bepirovirsen's more advanced Phase 3 status gives it a substantial lead time over these emerging approaches.

Expert Analysis: Bepirovirsen's Potential Role in Future CHB Treatment Guidelines

If the Phase 3 B-Well program is successful and bepirovirsen receives regulatory approval, it is poised to significantly alter the CHB treatment landscape and future clinical practice guidelines from organizations like the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL).[16]

Based on the current data, bepirovirsen would likely be recommended as a finite, 24-week course of treatment for patients with CHB who are on stable NA therapy and have low baseline HBsAg (≤3000 IU/mL). For patients who achieve a response, guidelines would likely recommend a period of continued NA therapy followed by NA cessation with careful monitoring for durable SVR. For patients with higher baseline HBsAg, bepirovirsen may find a role as the backbone of sequential therapies, where it is used to reduce HBsAg before the introduction of another immunomodulator to drive a deeper, more durable response.

Conclusion and Forward-Looking Recommendations

Bepirovirsen has emerged as a leading candidate in the global effort to develop a functional cure for chronic hepatitis B. Its unique, triple-action mechanism, which combines potent HBsAg suppression with direct immune stimulation, differentiates it from other investigational agents. The clinical development program, managed by GSK following its licensure from Ionis, has been robust and strategically executed. The landmark B-Clear trial successfully identified a patient population with a high probability of response, a finding that has been leveraged to optimize the design of the ongoing pivotal B-Well Phase 3 program.

The key inflection point for the program will be the data readout from the B-Well 1 and B-Well 2 trials, anticipated in late 2025. Positive results from these large-scale, confirmatory studies would pave the way for regulatory submissions in 2026 and could establish bepirovirsen as the first-in-class therapy capable of providing a finite treatment course leading to a functional cure for a significant subset of patients with CHB.

For stakeholders, bepirovirsen represents a high-potential asset in a therapeutic area with a massive unmet need. Its success would not only validate Ionis's ASO technology and GSK's late-stage development capabilities but would also mark a fundamental shift in the management of CHB—from lifelong suppression to the real possibility of a cure. The continued exploration of bepirovirsen in sequential and combination regimens further underscores its potential to serve as a foundational therapy in the evolving treatment paradigm for this widespread and life-threatening disease.

Appendices

Table 1: Summary of Key Bepirovirsen Clinical Trials

NCT Number	Trial Name / Acronym	Phase	Population	Key Objective(s)	Status (as of late 2024/early 2025)
NCT02981602	-	2	Treatment-naïve & NA-treated CHB	Assess safety, tolerability, PK, and preliminary antiviral activity.	Completed 39
NCT04544956	B-Fine	2a	HBeAg-negative CHB on stable NA therapy	Investigate intrahepatic virologic and immunologic mechanisms using FNA.	Recruiting 25
NCT04449029	B-Clear	2b	NA-treated & not-on-NA CHB	Assess efficacy (sustained HBsAg/HBV DNA loss) and safety of different dosing regimens.	Completed 45
NCT04676724	B-Together	2b	CHB on stable NA therapy	Assess efficacy and safety of sequential bepirovirsen followed by Peg-IFN.	Completed 55
NCT05630807	B-Well 1	3	NA-treated CHB with HBsAg ≤3000 IU/mL	Confirm efficacy and safety of bepirovirsen vs. placebo for functional cure.	Active, not recruiting 52
NCT05630820	B-Well 2	3	NA-treated CHB with HBsAg ≤3000 IU/mL	Confirm efficacy and safety of bepirovirsen vs. placebo for functional cure.	Active, not recruiting 60
NCT04954859	B-Sure	-	Responders from parent bepirovirsen studies	Evaluate long-term durability of treatment response.	Recruiting 69
NCT06537414	B-UNITED	2b	CHB on NA therapy	Assess sequential therapy with siRNA (daplusiran/tomligisiran) followed by bepirovirsen.	Recruiting 71
NCT06497504	B-Focus	2	HIV/HBV co-infection on ART	Evaluate efficacy and safety in co-infected participants.	Recruiting 23

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