Comprehensive Clinical and Developmental Analysis of Tobevibart (VIR-3434)

I. Executive Summary

Tobevibart, an investigational monoclonal antibody developed by Vir Biotechnology, represents a significant advancement in the therapeutic landscape for chronic viral hepatitis. When administered in combination with the small interfering RNA (siRNA) therapeutic elebsiran, it has demonstrated the potential to establish a new standard of care for Chronic Hepatitis D (CHD), the most aggressive form of viral hepatitis. The agent's unique, dual-pronged mechanism of action, which combines potent, pan-genotypic viral neutralization with a sophisticated, engineered capacity to engage and stimulate the host immune system, distinguishes it from existing and historical therapies. This multi-modal approach has produced compelling clinical results in the CHD setting, characterized by rapid, deep, and progressively sustained virologic suppression.

Key findings from the comprehensive development program indicate that the combination of tobevibart and elebsiran achieves a 100% virologic response rate at 24 weeks in patients with CHD, with a growing proportion achieving undetectable viral levels with longer treatment duration. This efficacy is coupled with a favorable and consistent safety profile, primarily featuring mild-to-moderate, transient adverse events. The profound potential of this regimen in CHD has been recognized by global regulatory bodies, with both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granting a full suite of expedited development designations, including Breakthrough Therapy, Fast Track, PRIME, and Orphan Drug status.

In contrast, the development program for Chronic Hepatitis B (CHB) has yielded more nuanced results. While the therapy demonstrated an ability to induce a functional cure in a subset of patients with low baseline hepatitis B surface antigen (HBsAg) levels, its efficacy in the broader CHB population was less pronounced. This outcome has prompted a strategic prioritization of the CHD program, for which a robust and strategically designed pivotal Phase III program, ECLIPSE, is underway. The ECLIPSE program is structured to establish the combination's superiority against both delayed treatment and the current European standard of care, bulevirtide, positioning tobevibart for global registration and market leadership in the treatment of CHD.

II. Introduction to Tobevibart: A Novel Immunomodulatory Antiviral Agent

2.1. Drug Profile and Development

Tobevibart is an investigational human immunoglobulin G1 ($IgG_1$) monoclonal antibody (mAb) being developed as a subcutaneously administered therapy for chronic viral hepatitis.[1] It is identified by the development codes VIR-3434 and BRII-877.[2] The therapeutic is a New Molecular Entity originated and developed by Vir Biotechnology, Inc., a clinical-stage immunology company with a focus on treating and preventing infectious diseases.[3] The antibody's design incorporates proprietary Fc engineering, including Xencor's Xtend™ technology, to optimize its pharmacokinetic and pharmacodynamic properties.[4] Tobevibart is classified within the therapeutic areas of antivirals and monoclonal antibodies, with a mechanism of action categorized as a virus internalization inhibitor.[2]

2.2. The Therapeutic Imperative in Chronic Hepatitis B and Delta Infections

Chronic Hepatitis B (CHB) remains a significant global public health challenge, affecting an estimated 254 million people worldwide and leading to long-term inflammatory liver disease.[2] The clinical course of CHB is often complicated by co-infection with the Hepatitis Delta Virus (HDV), a satellite virus that requires the Hepatitis B surface antigen (HBsAg) for its envelopment and propagation.[8] This co-infection leads to Chronic Hepatitis D (CHD), which is universally recognized as the most severe form of chronic viral hepatitis.[8]

Patients with CHD face an accelerated progression of liver disease, with a high risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma within years of infection.[2] The therapeutic landscape for CHD is exceptionally sparse, creating a profound unmet medical need.[11] For decades, the only widely available treatment has been pegylated interferon-alfa (PEG-IFNα), a therapy limited by significant side effects and low rates of sustained virologic response.[14] More recently, the entry inhibitor bulevirtide has been approved in Europe, but it is not available in the United States, and treatment options globally remain inadequate.[10]

The ultimate therapeutic objective in CHB is the achievement of a "functional cure," a state defined by the sustained loss of serum HBsAg and undetectable HBV DNA following a finite duration of treatment.[9] Attaining this goal necessitates a therapeutic strategy that extends beyond simple viral suppression. It requires a multi-faceted approach capable of reducing the high antigenic burden of HBsAg, which drives immune exhaustion, and actively stimulating the host's HBV-specific T and B cell responses to establish long-term immune control.[16] The development of tobevibart was undertaken with this high therapeutic bar in mind, aiming to address the critical deficiencies in the current treatment paradigms for both CHB and CHD.

III. A Dual-Pronged Mechanism of Action: Viral Neutralization and Immune Engagement

The therapeutic potential of tobevibart is rooted in a sophisticated, multi-modal mechanism of action that combines direct antiviral activity with potent immunomodulatory functions. This design represents a deliberate strategic shift away from therapies that merely suppress viral replication towards an approach that actively engages the host immune system to achieve durable, off-treatment control, aligning with the principles of a functional cure.

3.1. Direct Antiviral Activity: HBsAg Targeting and Entry Inhibition

The foundational mechanism of tobevibart is its high-affinity binding to the Hepatitis B surface antigen (HBsAg).[1] The antibody targets a conserved, discontinuous epitope located within the antigenic loop of HBsAg, a structure present on all forms of the protein (small, medium, and large).[16] This broad targeting allows tobevibart to exert pan-genotypic activity, effectively neutralizing virions from all known genotypes of both HBV and HDV.[8] Preclinical in vitro studies have quantified this potent neutralizing activity, demonstrating half-maximal effective concentrations ($EC_{50}$) in the low nanogram-per-milliliter range (1.1 to 4.6 ng/mL) against all tested HDV genotypes.[8]

By binding to HBsAg on the surface of viral particles, tobevibart physically obstructs the interaction between the virus and its entry receptor on the surface of hepatocytes.[6] This action effectively inhibits viral entry, classifying tobevibart as a virus internalization inhibitor.[2] This is a critical function, as HDV is entirely dependent on the HBsAg envelope for its lifecycle, including cell entry and assembly of new virions.[8]

3.2. Engineered Fc Domain for Enhanced Immunomodulation

Beyond its direct neutralizing capacity, tobevibart possesses a specially engineered Fc (fragment, crystallizable) domain designed to transform the antibody from a passive antiviral agent into an active immunomodulator. This engineering involves two key modifications:

1. Xtend™ Technology (LS Mutation): The inclusion of the M428L and N434S mutations in the Fc region significantly extends the antibody's serum half-life.[16] This pharmacokinetic enhancement allows for less frequent subcutaneous administration (e.g., every two or four weeks), improving its potential for patient convenience and adherence.[4]
2. GAALIE Mutation: The incorporation of the G236A, A330L, and I332E mutations fundamentally alters the antibody's interaction with the immune system.[16] This "GAALIE" modification is designed to enhance effector functions by increasing the antibody's binding affinity for activating Fc gamma receptors (FcγRs), specifically FcγRIIa and FcγRIIIa, which are expressed on various immune cells. Concurrently, it decreases binding to the inhibitory FcγRIIb.[2]

This engineered Fc functionality enables a cascade of immune-stimulating events. First, tobevibart cross-links HBsAg virions and subviral particles, forming immune complexes (ICs) in the circulation.[16] The enhanced affinity of the GAALIE Fc domain for activating FcγRs promotes the efficient binding and uptake of these ICs by phagocytic immune cells, such as neutrophils and monocytes.[2] This process is intended to mediate the rapid clearance of circulating HBsAg, thereby reducing the high antigen load that is a primary driver of T-cell exhaustion in chronic hepatitis.[6]

Furthermore, the increased FcγR signaling upon IC binding has been shown in vitro to activate professional antigen-presenting cells, such as dendritic cells (DCs).[9] Activated DCs are critical for initiating an adaptive immune response. This Fc-dependent enhancement of T-cell responses is a cornerstone of the therapeutic strategy for CHB, aiming to break immune tolerance and restore the body's ability to control the virus long-term.[2] This immunomodulatory capacity effectively positions tobevibart to function as a therapeutic T-cell vaccine, a mechanism that is fundamental to the pursuit of a functional cure.[23]

IV. Clinical Development Program: From Preclinical Models to Pivotal Trials

4.1. Foundational Preclinical and Phase I Studies

The clinical development of tobevibart was predicated on a strong foundation of preclinical evidence. In vitro experiments utilizing primary human hepatocytes (PHHs) and in vivo studies in human liver-chimeric mouse models of HBV/HDV coinfection consistently demonstrated potent antiviral activity.[8] In these models, tobevibart, both as a single agent and in combination with elebsiran, produced significant, additive reductions in HDV RNA and HBsAg levels.[8] These foundational studies confirmed the drug's pan-genotypic activity and provided the essential proof-of-concept to advance into human trials.[8]

The Phase I program established the initial safety, tolerability, and pharmacokinetic profile of tobevibart in humans. The NCT04423393 study was the first-in-human trial, evaluating the agent in both healthy volunteers and patients with CHB.[26] Subsequently, the NCT05484206 study specifically assessed the impact of hepatic impairment on the drug's disposition. This trial administered a single dose of tobevibart, alone or with elebsiran, to participants with mild cirrhosis (Child-Pugh Class A) and matched healthy volunteers. The results indicated that mild hepatic impairment did not significantly alter the pharmacokinetic exposure of tobevibart and confirmed a favorable safety profile in this population.[1]

4.2. The Tobevibart Clinical Trial Pipeline

The clinical investigation of tobevibart has progressed through a series of well-defined trials, each designed to answer specific questions regarding its efficacy, safety, and optimal use in different patient populations. The overall program is characterized by a Phase II investigation in CHB and a more advanced program in CHD, which has now progressed to the pivotal Phase III stage.

Table 1: Overview of Key Tobevibart Clinical Trials
Trial Name / Identifier	Phase	Indication	Primary Objective	Status
MARCH (NCT04856085)	Phase II	Chronic Hepatitis B (CHB)	Evaluate potential for achieving a functional cure with combination regimens.	Ongoing, Data Readout
SOLSTICE (NCT05461170)	Phase II	Chronic Hepatitis D (CHD)	Evaluate the safety, tolerability, and efficacy of monotherapy and combination therapy.	Data Readout
ECLIPSE 1 (NCT06903338)	Phase III	Chronic Hepatitis D (CHD)	Registrational trial evaluating combination therapy versus delayed treatment.	Recruiting
ECLIPSE 2 (NCT07128550)	Phase III	Chronic Hepatitis D (CHD)	Registrational trial in patients not responding to bulevirtide.	Recruiting
ECLIPSE 3	Phase IIb	Chronic Hepatitis D (CHD)	Head-to-head comparison against bulevirtide in treatment-naïve patients.	Planned

V. Clinical Efficacy and Safety in Chronic Hepatitis Delta (SOLSTICE Trial)

The Phase II SOLSTICE trial (NCT05461170) has been instrumental in defining the therapeutic profile of tobevibart in CHD and has provided the compelling data necessary to advance into a registrational program. The results demonstrate that the combination of tobevibart and elebsiran induces a virologic response that is not only rapid and profound but also deepens progressively with continued treatment, justifying the combination strategy for Phase III development.

5.1. Study Design and Patient Demographics

SOLSTICE is a multi-center, open-label, randomized Phase II study designed to evaluate the safety, tolerability, and efficacy of tobevibart in adults with CHD.[4] The trial included cohorts evaluating tobevibart monotherapy (300 mg administered subcutaneously every two weeks) and combination therapy with elebsiran (tobeibart 300 mg plus elebsiran 200 mg, both administered subcutaneously every four weeks).[4] A key feature of the study population was the inclusion of a substantial proportion of patients (approximately 50%) with compensated cirrhosis, reflecting a real-world, difficult-to-treat cohort.[4] The co-primary endpoints were assessed at Week 24 and consisted of: 1) virologic response, defined as a reduction in HDV RNA of at least $2 \log_{10} IU/mL$ from baseline or HDV RNA levels below the limit of detection (LOD), and 2) biochemical response, defined as the normalization of alanine aminotransferase (ALT) levels.[20]

5.2. Efficacy Analysis: Rapid, Deep, and Sustained Virologic Suppression

The efficacy results from the SOLSTICE trial, particularly from the combination therapy arms, have been exceptionally strong. The data reveal a clear trend of increasing viral suppression over time.

• Virologic and Biochemical Response: The combination regimen achieved a 100% virologic response rate at the Week 24 primary endpoint, a result that was sustained at all subsequent time points, including Week 36 and Week 60.[20] ALT normalization was achieved in 47% of participants in the combination de novo cohort by Week 24, with rates sustained at Week 36.[20]
• Depth and Durability of Response: The most compelling finding was the progressive deepening of the virologic response with longer treatment duration. The proportion of patients achieving HDV RNA Target Not Detected (TND)—the most stringent measure of viral clearance—steadily increased from 41% at Week 24, to 64% at Week 36, and ultimately to 80% in a rollover cohort that reached Week 60.[20] This kinetic profile suggests that the therapy is not merely suppressive but is actively clearing the virus over time, which may translate to a higher potential for durable off-treatment responses.
• Combined Endpoints: The protocol-defined combined endpoint of virologic response plus ALT normalization was achieved by 47% of participants in the combination arm at Week 24. A more stringent composite endpoint, requiring both TND and ALT normalization, was achieved by 19% at Week 24, a figure that rose to 27% by Week 36 and 40% by Week 60 in the rollover cohort, further underscoring the benefit of continued therapy.[29]

Table 2: Summary of Key Efficacy Endpoints from the SOLSTICE Phase II Trial (Combination Therapy Arms)
Efficacy Endpoint	Week 12	Week 24	Week 36	Week 60 (Rollover Cohort)
Virologic Response (≥2 log drop or <LOD)	100%	100%	100%	100%
HDV RNA < LLOQ	52%	100%	N/A	N/A
HDV RNA < LOD	37%	91%	N/A	N/A
HDV RNA TND	15%	41%	64%	80%
ALT Normalization	44%	47%	Sustained	N/A
Stringent Combined Endpoint (TND + ALT Norm)	N/A	19%	27%	40%
Data compiled from sources.20 LLOQ = Lower Limit of Quantification; LOD = Limit of Detection; TND = Target Not Detected; N/A = Not Available.

5.3. Safety and Tolerability in the CHD Population

Across the SOLSTICE trial, tobevibart, both as monotherapy and in combination with elebsiran, was generally well tolerated.[21] The safety profile was consistent with previous studies, with no new or unexpected safety signals emerging.[28] Treatment-emergent adverse events (TEAEs) were predominantly mild (Grade 1) or moderate (Grade 2) in severity and were transient in nature.[21] The most frequently reported TEAE was influenza-like illness.[28] Importantly, there were no treatment-related serious adverse events (SAEs), no discontinuations due to adverse events in the combination arms, and no observations of ALT flares, which can be a sign of drug-induced liver injury.[21]

VI. Pursuit of a Functional Cure in Chronic Hepatitis B (MARCH Trial)

The MARCH trial (NCT04856085) was designed to evaluate the potential of tobevibart-based combination regimens to achieve the ambitious goal of a functional cure in patients with CHB. While the study demonstrated the biological activity of the regimen and its ability to induce HBsAg loss in certain patients, the overall results highlighted the profound challenge of curing CHB and prompted a strategic re-evaluation of the program's immediate path forward.

6.1. Study Design and Therapeutic Strategy

MARCH is a Phase II, multi-center, open-label study investigating various regimens containing tobevibart and elebsiran.[25] Part B of the trial, which provided the key efficacy data, focused on two primary treatment strategies administered for up to 48 weeks: a "doublet" regimen of tobevibart (300 mg every four weeks) plus elebsiran (200 mg every four weeks), and a "triplet" regimen that added weekly pegylated interferon alfa (PEG-IFNα) to the doublet combination.[6] The primary endpoint was a stringent measure of functional cure: the proportion of participants with sustained HBsAg loss (seroclearance) at 24 weeks after the completion of all therapy.[6]

6.2. Efficacy Analysis: HBsAg Loss and Functional Cure Rates

The results of the MARCH trial were highly dependent on patients' baseline HBsAg levels. At the end of the 48-week treatment period, HBsAg loss was achieved in 39% of patients on the doublet regimen and 46% on the triplet regimen, but only among the subgroup of patients who started the trial with low baseline HBsAg levels (defined as $<1,000 IU/mL$).[25]

The more critical data came from the 24-week post-treatment follow-up period, which assessed the durability of the response. As expected, the rates of sustained response were lower than the end-of-treatment rates and remained concentrated in the low-baseline HBsAg subgroup. This outcome demonstrates that while the therapy can be effective, its ability to induce a durable cure is, at present, largely confined to a specific patient subset. In the face of these results, and in stark contrast to the overwhelmingly positive data from the CHD program, Vir Biotechnology announced a strategic decision to not advance the CHB program into Phase III development without securing a global partner, thereby prioritizing resources for the more promising CHD indication.[35]

Table 3: Summary of Key Efficacy Endpoints from the MARCH Phase II Trial (24 Weeks Post-Treatment)
Efficacy Endpoint	Doublet Regimen (All Patients)	Doublet Regimen (Baseline HBsAg <1000 IU/mL)	Triplet Regimen (All Patients)
HBsAg Loss (Sustained)	8%	17%	16%
Functional Cure (Sustained)	4%	11%	10%
Data compiled from sources.6

6.3. Safety and Tolerability in the CHB Population

The safety profile observed in the MARCH trial was consistent with that seen in other studies of tobevibart and elebsiran.[6] No new safety concerns were identified throughout the study.[25] Treatment-emergent adverse events were reported to be generally mild or moderate in severity.[25]

VII. The Path to Registration: The ECLIPSE Phase III Program for CHD

Following the highly successful outcomes of the SOLSTICE trial, Vir Biotechnology has initiated the ECLIPSE program, a comprehensive and strategically sophisticated global Phase III program designed to secure regulatory approval for the tobevibart and elebsiran combination in CHD.[5] The program is not a monolithic trial but a suite of three distinct studies, each tailored to address specific clinical questions and navigate the different regulatory and commercial landscapes of major global markets, particularly the United States and Europe.

7.1. Program Overview

The ECLIPSE registrational program is designed to evaluate the safety and efficacy of the tobevibart plus elebsiran combination therapy against relevant comparators to support submissions to global regulatory agencies.[5] It comprises two pivotal Phase III trials (ECLIPSE 1 and ECLIPSE 2) and a supportive Phase IIb trial (ECLIPSE 3).[5]

7.2. ECLIPSE 1 (NCT06903338): Establishing Efficacy vs. Control

ECLIPSE 1 is a randomized, open-label Phase III study that serves as the primary registrational trial for regions where there is no approved standard of care for CHD, most notably the United States.[5] The study compares immediate treatment with the tobevibart and elebsiran combination against a delayed treatment control arm.[38] This design is ethically and regulatorily appropriate for the U.S. market, where the primary competitor is essentially no treatment.[10] The primary endpoint is a combined virologic and biochemical response at Week 48, which, if met, is intended to form the basis of a Biologics License Application (BLA) to the FDA.[38]

7.3. ECLIPSE 2 (NCT07128550): Targeting the Bulevirtide-Experienced Population

ECLIPSE 2 is a pivotal Phase III trial specifically designed for the European market and other regions where the entry inhibitor bulevirtide is an approved therapy.[5] The trial targets a clear unmet need within this market: patients who have not achieved an adequate virologic response (i.e., viral suppression) despite receiving bulevirtide monotherapy for at least 24 weeks.[5] In this randomized, open-label study, participants will either switch to the tobevibart and elebsiran combination or continue on bulevirtide.[37] The primary endpoint is the achievement of HDV RNA TND at Week 24.[37] A positive result in this trial would position the combination as a critical second-line therapy for bulevirtide non-responders.

7.4. ECLIPSE 3: Head-to-Head Superiority and Market Access

ECLIPSE 3 is a planned Phase IIb study with a highly ambitious and commercially focused objective: to establish the superiority of the tobevibart and elebsiran combination over bulevirtide in treatment-naïve CHD patients.[5] While not a primary registrational trial, this head-to-head comparison is strategically crucial. Demonstrating superior efficacy in a first-line setting could displace bulevirtide as the standard of care in Europe and provide powerful data to support premium pricing and favorable reimbursement decisions from payers in key markets.[5] This three-pronged approach maximizes the probability of regulatory success and commercial uptake across diverse global markets.

VIII. Global Regulatory Status and Expedited Pathways

The promising clinical profile of the tobevibart and elebsiran combination for CHD has been met with significant enthusiasm from major global regulatory agencies, resulting in the granting of a full complement of expedited development and review designations.

8.1. United States Food and Drug Administration (FDA)

• Investigational New Drug (IND) Clearance: The FDA cleared the IND application for the combination therapy in June 2024, enabling the initiation of clinical trials, including the pivotal ECLIPSE 1 study, in the United States.[12]
• Fast Track Designation: Granted in June 2024, this designation facilitates more frequent interactions with the FDA and allows for a rolling review of the marketing application, potentially accelerating the path to approval.[12]
• Breakthrough Therapy Designation: Awarded in December 2024, this is one of the FDA's most significant designations. It is reserved for therapies that demonstrate substantial improvement over available treatments for a serious condition based on preliminary clinical evidence. This designation provides all the benefits of Fast Track, plus more intensive FDA guidance on creating an efficient drug development program.[11]

8.2. European Medicines Agency (EMA)

• Orphan Drug Designation: The EMA's Committee for Orphan Medicinal Products (COMP) issued a positive opinion on the orphan drug application in November 2024, with the formal designation (EU/3/24/3012) granted on December 13, 2024.[10] This status provides development incentives, including scientific advice, reduced fees, and a potential ten years of market exclusivity in the EU upon approval.
• Priority Medicines (PRIME) Designation: Granted in December 2024, the PRIME scheme is the EMA's equivalent of the FDA's Breakthrough Therapy designation. It offers early and enhanced scientific and regulatory support to developers of promising medicines that target a high unmet medical need, with the goal of expediting patient access to transformative treatments.[11]

8.3. Other Jurisdictions (e.g., Australia)

The available documentation does not contain specific information regarding regulatory submissions or the approval status of tobevibart with Australia's Therapeutic Goods Administration (TGA).[7]

IX. Synthesis and Forward-Looking Analysis

9.1. Consolidated Assessment of Tobevibart's Profile

The comprehensive development program for tobevibart has established a clear and compelling profile, particularly for its lead indication in Chronic Hepatitis D.

• Strengths: The primary strength of the tobevibart/elebsiran regimen is its exceptional efficacy in CHD, demonstrating rapid, deep, and durable virologic suppression in a patient population with a very high unmet need. This clinical performance is underpinned by a novel, multi-modal mechanism of action that combines direct viral neutralization with immune system activation. The therapy's favorable safety and tolerability profile, coupled with the strong endorsement from both the FDA and EMA through a complete set of expedited program designations, significantly de-risks its path to market.
• Challenges/Weaknesses: The primary challenge is that optimal efficacy requires a combination regimen with elebsiran, which introduces complexity in manufacturing, co-formulation or co-packaging, and commercialization strategy compared to a monotherapy. Additionally, the clinical data in the broader CHB population, while promising in a select subgroup, was not robust enough to support independent late-stage development, thereby constraining the therapy's immediate potential in that much larger market.

9.2. Competitive Context and Future Outlook

The current standard of care for CHD is inadequate. PEG-IFNα is poorly tolerated and offers low cure rates.[15] Bulevirtide (Hepcludex), approved in Europe, is a first-in-class entry inhibitor that blocks the sodium taurocholate co-transporting polypeptide (NTCP) receptor, preventing both HBV and HDV from entering hepatocytes.[55] While a major step forward, clinical data suggest that bulevirtide's virologic response can be slow to emerge, and a significant portion of patients may not achieve full viral suppression even with prolonged treatment.[59]

The tobevibart and elebsiran combination is positioned to be superior to this standard. Its value proposition is centered on delivering a faster, deeper, and potentially more durable response. The combination's multi-pronged attack—blocking viral entry (tobeibart), shutting down HBsAg production (elebsiran), and stimulating an anti-viral immune response (tobeibart's engineered Fc domain)—is mechanistically more comprehensive than the singular entry inhibition of bulevirtide.

In conclusion, tobevibart, as a core component of a combination regimen with elebsiran, is poised to become the new global standard of care for Chronic Hepatitis D. The strength of the Phase II clinical data, the sophisticated design of the Phase III ECLIPSE program, and the powerful regulatory tailwinds create a clear and compelling trajectory toward approval and commercialization. The successful development of this therapy would represent a transformative breakthrough for patients afflicted with this devastating liver disease. While its future in the Chronic Hepatitis B arena is contingent upon securing a strategic partnership, its path forward in hepatitis delta marks it as one of the most important late-stage antiviral assets currently in development.

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