Comprehensive Report on ALN-HBV-02 (Elebsiran/VIR-2218/BRII-835): An Investigational RNAi Therapeutic for Chronic Hepatitis B and D

1. Executive Summary

ALN-HBV-02, also known by its developmental codenames VIR-2218 and BRII-835, and the proposed international non-proprietary name elebsiran, is an investigational small interfering RNA (siRNA) therapeutic. Originating from Alnylam Pharmaceuticals and co-developed with Vir Biotechnology and Brii Biosciences, ALN-HBV-02 targets hepatitis B virus (HBV) transcripts, primarily aiming to reduce hepatitis B surface antigen (HBsAg) levels. A key innovation is its Enhanced Stabilization Chemistry Plus (ESC+) technology, designed to improve hepatic safety and specificity compared to its precursor, ALN-HBV. Administered subcutaneously, ALN-HBV-02 has demonstrated potent HBsAg reduction in clinical trials for chronic hepatitis B (CHB). While monotherapy shows significant HBsAg knockdown, achieving functional cure (sustained HBsAg loss and anti-HBs seroconversion) typically requires combination with immunomodulators (e.g., pegylated interferon-alfa, therapeutic vaccines) or other antiviral agents (e.g., HBsAg-targeting monoclonal antibodies like tobevibart). The safety profile of ALN-HBV-02 monotherapy appears favorable; in combination regimens, adverse events are generally consistent with the known profiles of the partner drugs. Notably, the combination of elebsiran and tobevibart has shown substantial promise for chronic hepatitis D (CHD), leading to expedited regulatory pathways, including FDA Breakthrough Therapy and Fast Track designations, and EMA PRIME status, with global Phase 3 trials (ECLIPSE program) underway. Ongoing research continues to define optimal combination strategies and long-term outcomes, positioning ALN-HBV-02 as a potentially pivotal component in future curative regimens for CHB and a new therapeutic option for CHD.

2. Introduction to ALN-HBV-02 (Elebsiran/VIR-2218/BRII-835)

2.1. Overview as an Investigational RNAi Therapeutic

ALN-HBV-02 is an investigational therapeutic agent based on small interfering RNA (siRNA) technology, currently under clinical development for the treatment of chronic hepatitis B virus (HBV) infection.[1] More recently, its application has been extended to investigations for chronic hepatitis D virus (HDV) infection, a condition that invariably occurs as a co-infection with HBV and relies on HBV for its lifecycle.[3] The therapeutic strategy of ALN-HBV-02 leverages the natural cellular mechanism of RNA interference (RNAi) to achieve targeted gene silencing. This approach aims to directly inhibit the production of viral proteins, offering a distinct mechanism of action compared to existing antiviral therapies.[5] ALN-HBV-02 is administered via subcutaneous injection, a route that offers potential for improved patient convenience and compliance in the management of chronic viral infections.[4]

2.2. Nomenclature: Synonyms and Developmental Codonames

The compound ALN-HBV-02 is identified by several names across scientific literature, clinical trial registries, and company communications, reflecting its developmental history and collaborative partnerships. These synonyms include:

• ALN-HBV-02: This was the initial designation assigned by Alnylam Pharmaceuticals, the originator of the compound.[1]
• VIR-2218: This is the development codename predominantly used by Vir Biotechnology, which has taken a leading role in its clinical advancement.[1]
• Elebsiran: This is the proposed international non-proprietary name (INN) for VIR-2218, increasingly used in recent publications and regulatory discussions.[6]
• BRII-835: This codename is used by Brii Biosciences, which is responsible for the development and commercialization of the drug in the Greater China region.[8]

Additional synonyms such as "ALN HBV" and "ALN-81890 FREE ACID" have also been noted in some databases.[5] The consistent appearance of these varied designations across different sources underscores the importance of recognizing them as referring to the same therapeutic entity when reviewing the evolving body of research.[1]

2.3. Originator and Collaborative Development Landscape

ALN-HBV-02 was originated by Alnylam Pharmaceuticals, Inc., a biotechnology company specializing in the development of RNAi therapeutics.[5] The subsequent clinical development and potential commercialization of ALN-HBV-02 involve a multi-company collaborative effort:

• Vir Biotechnology: A significant strategic alliance was formed between Alnylam Pharmaceuticals and Vir Biotechnology to advance RNAi therapeutics for infectious diseases, with ALN-HBV-02 being a key program within this collaboration. Under the terms of their agreement, valued at up to $1 billion, Alnylam was responsible for leading ALN-HBV-02 to the Investigational New Drug (IND) application filing. Subsequently, Vir Biotechnology assumed responsibility for progressing ALN-HBV-02 through human proof-of-concept studies and further clinical development for both CHB and CHD.[1] Alnylam retains the option to participate in a profit-sharing arrangement prior to the initiation of Phase 3 trials for the HBV indication.[9]
• Brii Biosciences: Brii Biosciences secured exclusive rights from Vir Biotechnology to develop and commercialize BRII-835 (elebsiran) within the Greater China territory, encompassing mainland China, Hong Kong, Macau, and Taiwan.[6] Brii Biosciences is actively conducting clinical trials in this region, including the Phase 2 study NCT04507269, to evaluate the compound in local patient populations.[16]

The development of ALN-HBV-02 through such a multi-company collaboration model is indicative of several strategic considerations prevalent in modern pharmaceutical development. The substantial financial investment and inherent risks associated with bringing novel therapeutics to market, particularly for widespread and challenging diseases like CHB, often necessitate such partnerships. This model allows for the pooling of financial resources and the leveraging of diverse expertise. Alnylam contributes its foundational RNAi platform technology and discovery capabilities.[9] Vir Biotechnology brings its experience in infectious disease drug development and clinical trial execution on a global scale.[9] Brii Biosciences offers specialized knowledge of the clinical and regulatory landscape in Greater China, a region with a particularly high prevalence of HBV, thereby facilitating efficient trial enrollment and market access strategies.[13] For the originating company, Alnylam, this collaborative approach enables them to maintain focus on their broader pipeline while retaining significant potential future value from ALN-HBV-02 through mechanisms like profit-sharing options.[9] While complex, these collaborations aim to optimize resource allocation, accelerate development timelines, and maximize the therapeutic's potential reach to patients globally. The success of such endeavors relies heavily on clearly defined roles, responsibilities, and effective communication channels among the partners.

3. Mechanism of Action and Preclinical Rationale

3.1. The RNA Interference (RNAi) Pathway

ALN-HBV-02 is a synthetic small interfering RNA (siRNA) molecule designed to harness the endogenous cellular pathway of RNA interference (RNAi).[5] RNAi is a highly conserved biological process in eukaryotic cells that mediates sequence-specific post-transcriptional gene silencing. Upon administration and delivery into hepatocytes, the double-stranded siRNA molecule is processed by an enzyme called Dicer and incorporated into a multi-protein complex known as the RNA-Induced Silencing Complex (RISC). The antisense (or guide) strand of the siRNA within RISC then directs the complex to bind to messenger RNA (mRNA) molecules that have a complementary sequence. This binding leads to the catalytic cleavage and subsequent degradation of the target viral mRNA.[17] By destroying the viral mRNA, ALN-HBV-02 effectively prevents its translation into viral proteins, thereby inhibiting viral replication and pathogenic processes.

3.2. Targeting Hepatitis B Surface Antigen (HBsAg) and HBV Proteins

The primary molecular target of ALN-HBV-02 is the messenger RNA (mRNA) encoding the Hepatitis B Surface Antigen (HBsAg).[5] Some sources further specify that it targets the L-HBsAg (Large HBsAg) transcript.[8] The HBV genome is highly compact and utilizes overlapping reading frames, meaning that targeting a conserved region within the HBV transcripts, such as that encoding HBsAg, can lead to the degradation of multiple viral mRNAs. Consequently, ALN-HBV-02 is designed to inhibit the expression of all HBV proteins, including HBsAg (Small, Middle, and Large forms), Hepatitis B e-antigen (HBeAg), core protein (HBcAg), and the viral DNA polymerase.[2] This broad-spectrum inhibition of viral gene products differentiates RNAi therapeutics like ALN-HBV-02 from nucleos(t)ide analogues (NUCs), which primarily target the viral polymerase and suppress HBV DNA replication but have limited impact on HBsAg production from integrated HBV DNA or cccDNA.[17] Reduction of HBsAg is considered a critical therapeutic goal in CHB, as HBsAg is implicated in maintaining immune tolerance and contributing to liver damage.

3.3. Enhanced Stabilization Chemistry Plus (ESC+) Technology

ALN-HBV-02 (VIR-2218) is a GalNAc-siRNA conjugate that incorporates Alnylam's proprietary Enhanced Stabilization Chemistry Plus (ESC+) technology.[4] The N-acetylgalactosamine (GalNAc) trivalent ligand is conjugated to the siRNA, enabling targeted delivery to hepatocytes. GalNAc binds with high affinity to the asialoglycoprotein receptor (ASGPR), which is abundantly expressed on the surface of liver cells, thereby facilitating receptor-mediated endocytosis and efficient uptake of the siRNA into the target cells.[17]

The ESC+ chemical modifications are a key feature of ALN-HBV-02. These modifications include the strategic incorporation of glycol nucleic acid (GNA) residues, particularly within the "seed region" of the siRNA's antisense strand.[5] The seed region (typically nucleotides 2-8 of the antisense strand) plays a crucial role in target mRNA recognition and binding. However, it is also the primary site for unintended binding to partially complementary off-target mRNAs, which can lead to undesired gene silencing and potential toxicity.

The purpose of ESC+ technology is to mitigate these off-target effects. By introducing modifications like GNA, the binding affinity of the seed region to off-target sequences is reduced (destabilized), thereby improving the specificity of the siRNA for its intended HBV target.[5] Importantly, these modifications are designed to maintain or minimally affect the on-target silencing activity. The anticipated benefits of this enhanced specificity include an improved hepatic safety profile, particularly a reduction in the risk of alanine aminotransferase (ALT) elevations, and consequently, an increased therapeutic index (the ratio of toxic dose to therapeutic dose) for the drug.[4]

3.4. Evolution from ALN-HBV to ALN-HBV-02: A Critical Safety-Driven Redesign

The development of ALN-HBV-02 (VIR-2218) was a direct consequence of safety observations made with its precursor compound, ALN-HBV. ALN-HBV shared an identical siRNA sequence with VIR-2218 but did not incorporate the ESC+ chemical modifications.[18] In a Phase 1/2 clinical trial (NCT02826018), ALN-HBV was administered to healthy volunteers and patients with CHB. This study revealed dose-dependent, transient, and asymptomatic elevations in ALT levels, a biomarker of potential liver injury.[5] These findings led to the termination of the ALN-HBV-001 study.[5]

Following this, ALN-HBV-02 (VIR-2218) was developed as a "redesigned" version of ALN-HBV, specifically incorporating the ESC+ technology to address the observed hepatotoxicity concerns.[5] Comparative studies were conducted to evaluate the impact of these chemical modifications:

• In vitro studies: RNA sequencing analysis in HepG2.2.15 cells (an HBV-expressing cell line) demonstrated that VIR-2218 treatment resulted in fewer differentially expressed genes and a lower magnitude of gene dysregulation compared to ALN-HBV. This supported the hypothesis that ESC+ modifications reduce off-target effects.[18]
• In vivo animal studies: In chimeric mice with humanized livers, administration of VIR-2218 led to markedly lower human ALT1 levels compared to ALN-HBV at equivalent dose levels (up to 100 mg/kg). A dose-dependent increase in h-ALT1 was observed with ALN-HBV, but not with VIR-2218.[18]
• Healthy volunteer studies: In human clinical trials, VIR-2218 showed a substantially decreased propensity to cause ALT elevations at dose levels anticipated to be clinically relevant, compared to ALN-HBV.[18]

This improved safety profile, particularly concerning hepatic safety, was a pivotal factor that allowed the therapeutic program to be reintroduced into clinical development under the designation ALN-HBV-02/VIR-2218.[5]

The evolution from ALN-HBV to ALN-HBV-02 highlights the critical importance of chemical modification strategies in optimizing the viability of RNAi therapeutics. The initial hepatotoxicity signals observed with ALN-HBV [5], likely driven by off-target seed-mediated effects [5], posed a significant challenge that could have led to the abandonment of the program. However, by identifying the molecular basis of the toxicity and engineering a solution through ESC+ technology – specifically modifying the seed region with GNA to reduce off-target binding while preserving on-target potency [5] – Alnylam was able to significantly improve the drug's safety profile. Preclinical and subsequent early clinical data directly validated this approach, showing fewer off-target gene changes and lower ALT elevations with VIR-2218 compared to its predecessor.[18] This iterative process of drug design, problem identification, chemical solution engineering, and validation underscores the maturation of RNAi technology. The ability to fine-tune siRNA molecules to enhance their therapeutic index was fundamental to overcoming the safety hurdles and ensuring the continued development of this promising HBV therapeutic. Without such advancements in chemical modification, the ALN-HBV program might have been permanently discontinued.

4. Therapeutic Indications and Patient Populations

4.1. Primary Focus: Chronic Hepatitis B Virus (HBV) Infection

ALN-HBV-02 (elebsiran/VIR-2218/BRII-835) is primarily being developed for the treatment of chronic hepatitis B virus (HBV) infection.[1] Clinical trials investigating ALN-HBV-02 for CHB have typically enrolled adult participants, often within an age range of 18 to 65 years.[12] These patient populations include individuals who are HBeAg-positive or HBeAg-negative and are frequently on stable, long-term nucleos(t)ide reverse transcriptase inhibitor (NRTI) therapy. A common characteristic of these enrolled patients is suppressed HBV DNA levels (often <90 IU/mL or below the lower limit of quantification) but with persistent HBsAg, indicating ongoing viral protein production and immune dysregulation.[11] Initial studies predominantly focused on patients without cirrhosis to establish safety and efficacy in a less complex patient group.[12]

The overarching therapeutic goal in the management of CHB is to achieve a "functional cure." This is generally defined as the sustained loss of serum HBsAg (HBsAg seroclearance), ideally accompanied by the development of antibodies against HBsAg (anti-HBs seroconversion), and the maintenance of undetectable HBV DNA levels in the serum after cessation of all antiviral therapy.[7] Achieving functional cure is believed to signify a state of durable immune control over the virus, potentially reducing the long-term risks of liver disease progression, cirrhosis, and hepatocellular carcinoma (HCC).

4.2. Emerging Application: Chronic Hepatitis D Virus (HDV) Co-infection

A significant and rapidly advancing area of development for ALN-HBV-02 (elebsiran) is its use in the treatment of chronic hepatitis D virus (HDV) infection. In this indication, elebsiran is typically investigated as part of a combination regimen, most notably with tobevibart (VIR-3434), an investigational monoclonal antibody that targets HBsAg.[2]

HDV is a defective RNA virus, often referred to as a satellite virus, which requires the helper functions of HBV for its own replication, assembly, and transmission. Specifically, HDV utilizes the HBsAg of HBV as its envelope protein.[3] Therefore, a therapeutic strategy that reduces HBsAg levels, such as that employed by ALN-HBV-02, is mechanistically poised to directly inhibit the HDV lifecycle by depriving it of an essential component for virion formation and propagation.[3] Clinical trials evaluating elebsiran for CHD are enrolling patients co-infected with HBV and HDV, including those with compensated cirrhosis, reflecting the often more advanced liver disease seen in this population.[4]

The dual indication potential of ALN-HBV-02, targeting both CHB and CHD, has led to a nuanced development strategy. While CHB represented the initial and broader target, the development of elebsiran in combination with tobevibart for CHD has gained considerable momentum, evidenced by its progression to Phase 3 registrational trials.[2] Several factors may contribute to this strategic emphasis. Firstly, CHD is recognized as the most severe form of chronic viral hepatitis, characterized by a more rapid progression to cirrhosis, liver failure, and HCC compared to HBV monoinfection. Treatment options for CHD are extremely limited, creating a high unmet medical need.[3] This urgency can facilitate more streamlined regulatory pathways if promising efficacy is demonstrated. Secondly, the direct mechanistic link between HBsAg and HDV replication makes HBsAg-lowering therapies like elebsiran particularly relevant. Combining this with an HBsAg-neutralizing antibody like tobevibart offers a potent dual mechanism of action against both viruses. Thirdly, achieving high rates of functional cure in the diverse CHB population has proven to be a complex challenge, often necessitating intricate multi-drug combinations and careful patient stratification based on baseline viral and host factors.[8] In contrast, the efficacy signals observed in early HDV trials with the elebsiran-tobebevibart combination, such as high rates of HDV RNA suppression [26], may have presented a clearer and more rapid path to demonstrating significant clinical benefit. This strategic prioritization for HDV does not necessarily diminish the importance of the CHB program but rather reflects an adaptive development approach, capitalizing on strong data and addressing a critical unmet need in a distinct patient population.

5. Clinical Development Program: An Overview

5.1. Progression Through Clinical Phases

ALN-HBV-02, under its various codenames (VIR-2218, elebsiran, BRII-835), has progressed through a comprehensive clinical development program. For CHB, the drug has undergone extensive Phase 1 studies, initially in healthy volunteers to assess safety and pharmacokinetics, followed by studies in CHB patients.[5] Subsequently, numerous Phase 2 trials have been conducted to evaluate its efficacy in reducing HBsAg and other viral markers, both as a monotherapy and in combination with other agents.[1]

For the CHD indication, the development trajectory, particularly for the combination of elebsiran with the monoclonal antibody tobevibart (VIR-3434), has been notably rapid. Following promising Phase 2 results, this combination has advanced into global Phase 3 registrational studies under the ECLIPSE program.[2]

5.2. Administration and Dosing Strategies

Across its clinical development, ALN-HBV-02 has been administered via subcutaneous (SC) injection.4

In Phase 2 trials for CHB, a common dosing regimen for VIR-2218 has been 200 mg administered every 4 weeks.11 Initial studies explored the impact of treatment duration, comparing shorter regimens (e.g., two doses) with longer ones (e.g., six doses).11 Subsequent combination studies have employed treatment periods ranging from 20 weeks up to 48 weeks or longer.12

For the Phase 3 ECLIPSE program in CHD, elebsiran is being administered at a dose of 200 mg SC every 4 weeks. This is given in combination with tobevibart, which is dosed at 300 mg SC every 4 weeks. The planned treatment duration in some contexts within this program extends up to 240 weeks (approximately 5 years), reflecting the chronic nature of the infection and the need to assess long-term efficacy and safety.27

5.3. Synopsis of Key Clinical Trials

Several key clinical trials have defined the development path of ALN-HBV-02:

• ALN-HBV-001 (NCT02826018): This was a Phase 1/2 study of the precursor compound, ALN-HBV, in healthy volunteers and CHB patients. Although terminated due to observations of ALT elevations, this study provided critical comparative safety data that highlighted the improved profile of the subsequently developed VIR-2218 with ESC+ technology.[5]
• VIR-2218-1001 (NCT03672188): This foundational Phase 1/2 study was instrumental in evaluating VIR-2218 (elebsiran).
• Part A involved single ascending doses in healthy volunteers, establishing initial safety, tolerability, and pharmacokinetic profiles.[17]
• Parts B and C assessed multiple ascending doses in HBeAg-negative and HBeAg-positive CHB patients, respectively, who were on stable NRTI therapy.[16]
• The study also included cohorts that directly compared VIR-2218 monotherapy against its combination with pegylated interferon-alfa (PEG-IFNα) over various treatment durations, providing key efficacy and safety data for these approaches.[12]
• VIR-2218-1005 (NCT04507269): Sponsored by Brii Biosciences, this Phase 2, randomized, placebo-controlled study was conducted in Mainland China. It aimed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of multiple doses of VIR-2218 (referred to as BRII-835 by Brii Bio) in adult CHB patients on NRTI therapy. The study was designed to be conducted in close collaboration with the broader regional VIR-2218-1001 study.[16]
• MARCH Study (Part B): This Phase 2 trial, conducted by Vir Biotechnology, focused on evaluating various combination therapies for CHB, prominently featuring tobevibart (VIR-3434) and elebsiran (VIR-2218), with or without the addition of PEG-IFNα. The primary goal was to assess the potential of these multi-drug regimens to achieve HBsAg loss and functional cure.[8]
• ENSURE Study (NCT04749368; CTR20243850 for ENHANCE component): This Phase 2a study, sponsored by Brii Biosciences, explored multiple therapeutic strategies. It evaluated elebsiran (BRII-835) as monotherapy, in combination with BRII-179 (an investigational HBV therapeutic vaccine), and also elebsiran in combination with PEG-IFNα in CHB patients. A notable aspect of this study was the investigation into whether baseline immune responsiveness, particularly to BRII-179, could predict treatment outcomes.[8]
• SOLSTICE Study (NCT05461170): This Phase 2 trial, led by Vir Biotechnology, is specifically designed to evaluate the efficacy, safety, and tolerability of tobevibart (VIR-3434) and elebsiran (VIR-2218), administered alone or in combination, in participants with chronic HDV infection.[3]
• ECLIPSE Program: Representing the advancement to late-stage development for CHD, this global Phase 3 registrational program was initiated by Vir Biotechnology for the combination of tobevibart and elebsiran. The program comprises three distinct trials:
• ECLIPSE 1: Compares the combination therapy against deferred treatment in regions with limited access to current HDV therapies.
• ECLIPSE 2: Evaluates switching to the combination therapy in CHD patients who have not achieved viral suppression with bulevirtide.
• ECLIPSE 3: A head-to-head trial comparing the combination therapy with bulevirtide in bulevirtide-naïve patients. The first patient in the ECLIPSE program was enrolled in March 2025.[2]

The clinical development pathway of ALN-HBV-02 illustrates an iterative and adaptive trial design strategy. Initial Phase 1/2 studies, such as NCT03672188, were crucial for establishing the monotherapy pharmacokinetics, safety profile, and fundamental efficacy in HBsAg reduction.[17] Recognizing the limitations of HBsAg reduction alone for achieving a functional cure in CHB, the program evolved to explore various hypothesis-driven combination strategies. These included pairing ALN-HBV-02 with immunomodulators like PEG-IFNα (to boost host immune responses, as seen in NCT03672188 and the ENSURE study), with monoclonal antibodies like tobevibart (for direct HBsAg targeting, as in the MARCH and SOLSTICE studies), and with therapeutic vaccines like BRII-179 (to actively stimulate HBV-specific immunity, as in the ENSURE study). Learnings from earlier studies or specific cohorts informed the design of subsequent investigations. For instance, the observation that longer durations of siRNA treatment tended to yield more profound and sustained HBsAg reduction [11] likely influenced the treatment durations in later, more complex combination trials. Similarly, the promising findings related to immune priming with BRII-179, suggesting it could identify patients more likely to achieve favorable outcomes [34], may lead to the development of patient enrichment strategies in future studies. The challenges encountered in achieving high rates of functional cure in the broad CHB population [8] have also likely contributed to the accelerated focus on the HDV indication, where the combination with tobevibart showed strong early signals. This adaptive approach, where clinical programs are refined based on emerging data and evolving understanding of the disease and drug mechanisms, is characteristic of complex therapeutic development.

6. Pharmacokinetics of ALN-HBV-02

The pharmacokinetic (PK) profile of ALN-HBV-02 (VIR-2218) in humans has been characterized primarily through the single ascending dose portion (Part A) of the Phase 1 study VIR-2218-1001 (NCT03672188) conducted in healthy volunteers.[17]

• Absorption: Following subcutaneous administration, VIR-2218 was rapidly absorbed, with the median time to reach peak plasma concentration (tmax​) observed to be between 4 and 7 hours.[17]
• Distribution: VIR-2218 demonstrated rapid and efficient distribution to the liver. This targeted delivery is attributed to the GalNAc ligand conjugated to the siRNA, which facilitates uptake by the asialoglycoprotein receptors (ASGPR) highly expressed on the surface of hepatocytes.[17]
• Metabolism: In plasma, a portion of VIR-2218 was observed to be converted to an active metabolite, identified as AS(N-1)3’VIR-2218. This metabolite reached its median tmax​ between 6 and 10 hours. The systemic exposure to this metabolite, as measured by plasma AUC0−12​ and Cmax​ values, was relatively low, constituting ≤ 12% of the parent VIR-2218 exposure.[17]
• Excretion: Both VIR-2218 and its metabolite AS(N-1)3’VIR-2218 were detectable in urine through the last measured time point, which was 1 week post-dose. Over the initial 0–24 hours post-dose, approximately 17–48% of the administered dose was recovered in the urine as unchanged VIR-2218. For single doses up to 600 mg, renal excretion appeared to be a minor route of elimination, with a combined 19–36% of the parent drug and its metabolite being excreted in the urine within 24 hours. However, at the highest dose tested (900 mg), this proportion increased to 55%, suggesting a potential transient saturation of the hepatic ASGPR-mediated uptake mechanism at very high doses, leading to increased systemic circulation and renal clearance.[17]
• Half-life: VIR-2218 exhibited a short median plasma half-life, ranging from 2 to 5 hours. Both the parent drug and its metabolite concentrations in plasma typically declined below the lower limit of quantification (LLOQ) within 48 hours post-dose.[17]
• Dose Proportionality: Pharmacokinetic parameters, including Area Under the Curve (AUC) and Cmax​, generally demonstrated an increase with escalating doses of VIR-2218, as indicated by data from various dose cohorts in the Phase 1 study.[17]
• Preclinical Pharmacokinetics: Prior to human studies, the pharmacokinetic properties of VIR-2218 were also evaluated in preclinical animal models, including rats and non-human primates (NHPs). These studies involved assessments of plasma and liver tissue concentrations of VIR-2218 and its metabolite.[17]

The pharmacokinetic profile of ALN-HBV-02 reveals several important characteristics relevant to its therapeutic application. The GalNAc conjugation ensures efficient and targeted delivery to hepatocytes, the primary site of HBV replication, following subcutaneous administration.[17] This liver-targeting is crucial for maximizing the drug's efficacy while minimizing potential exposure and effects in non-target tissues. Despite a short plasma half-life of 2-5 hours [17], ALN-HBV-02 achieves a prolonged pharmacodynamic effect, evidenced by sustained HBsAg reduction over weeks to months with infrequent dosing (e.g., every 4 weeks). This discrepancy between plasma PK and pharmacodynamic duration is a hallmark of well-designed RNAi therapeutics. Once the siRNA is delivered into the hepatocyte and loaded into the RISC, its intracellular stability and the persistence of the RISC-target mRNA silencing machinery dictate the duration of gene knockdown, which extends far beyond the time the drug is detectable in systemic circulation. The observation of potentially saturated liver uptake at the 900 mg dose, leading to increased renal excretion [17], is an important finding. It suggests that there might be an optimal dosing range to maximize hepatic delivery and efficacy, beyond which further dose escalation might not proportionally increase liver exposure and could lead to greater systemic exposure. Overall, the PK profile supports the feasibility of an infrequent subcutaneous dosing regimen, which is advantageous for patient adherence in the context of chronic diseases like HBV and HDV.

7. Clinical Efficacy in Chronic Hepatitis B

7.1. Monotherapy Efficacy (VIR-2218 / Elebsiran)

Clinical trials have evaluated VIR-2218 as a monotherapy for CHB, primarily focusing on its ability to reduce HBsAg levels in patients already on stable NRTI therapy with suppressed HBV DNA.

In the Phase 2 portion of the NCT03672188 study (Cohort 1), participants received six doses of VIR-2218 at 200 mg subcutaneously every 4 weeks for a total of 20 weeks. This regimen resulted in a mean maximum HBsAg reduction from baseline of -2.0 log10 IU/mL (95% CI –2.1 to –1.8).[19] However, no instances of HBsAg seroclearance were observed in this monotherapy cohort during the study period.[19]

Early data indicated that longer treatment durations yielded more significant and durable HBsAg reductions. A comparison between a two-dose and a six-dose regimen of VIR-2218 showed that while all participants in both groups achieved a >1 log10 IU/mL reduction in HBsAg, the six-dose regimen was associated with a greater mean maximum HBsAg reduction. Furthermore, 73% of participants receiving six doses of VIR-2218 maintained at least a 1 log10 IU/mL reduction in HBsAg from baseline through 40 weeks after the last dose, demonstrating a degree of sustained response.[11]

In addition to HBsAg reduction, VIR-2218 monotherapy also led to reductions in other viral biomarkers, such as HBeAg and HBV DNA, although the latter was typically already suppressed by concomitant NRTI therapy.[11] In one notable case, a patient receiving 200 mg of VIR-2218 experienced HBeAg loss at Week 24 and achieved anti-HBe seroconversion at Week 16, which was sustained through Week 48.[38]

Despite the potent HBsAg reduction, studies have suggested that siRNA-mediated HBsAg reduction alone, as achieved with VIR-2218 monotherapy, is associated with only minimal recovery of HBV-specific immune responses.[8] This observation underscores the rationale for exploring combination therapies.

7.2. Combination Therapy Efficacy

Recognizing the limitations of monotherapy in achieving functional cure, ALN-HBV-02 has been extensively studied in combination with various agents aimed at either further suppressing viral activity or stimulating host immune responses.

7.2.1. With Pegylated Interferon-alpha (PEG-IFNα)

The combination of VIR-2218 with PEG-IFNα has been investigated in multiple cohorts of the NCT03672188 study and the ENSURE study.

• In NCT03672188 (Cohorts 2-5), VIR-2218 (200 mg q4w) combined with PEG-IFNα (180 µg weekly) for durations ranging from 12 to 48 weeks consistently demonstrated greater mean maximum HBsAg declines compared to VIR-2218 monotherapy. These reductions ranged from -2.2 log10 IU/mL to -3.0 log10 IU/mL across the different combination cohorts.[19]
• Crucially, HBsAg seroclearance was achieved in 11 out of 64 (17.2%) participants receiving the VIR-2218 plus PEG-IFNα combination at any timepoint during the study. Of these, six participants (9.4% of the 64) maintained HBsAg seroclearance for at least 24 weeks after the end of treatment, indicating a durable response. Furthermore, 10 of the 11 participants (91%) who achieved HBsAg seroclearance also developed anti-HBs antibodies (seropositivity).[19]
• Among HBeAg-positive participants in these combination cohorts, 12 out of 26 (46%) experienced HBeAg seroclearance or anti-HBe seroconversion.[19]
• The ENSURE study, conducted by Brii Biosciences, also reported superior outcomes with elebsiran plus PEG-IFNα compared to PEG-IFNα alone. Mean HBsAg reductions at the end of treatment (EOT) were significantly greater in the combination arms (-2.47 to -3.01 log10 IU/mL) versus the PEG-IFNα monotherapy arm (-1.02 log10 IU/mL).[24] At 24 weeks post-EOT (Week 72 overall), HBsAg loss rates were 21.1-33.3% for the combination therapy compared to 5.6% for PEG-IFNα alone.[36]

7.2.2. With Therapeutic Vaccine (BRII-179 / VBI-2601)

The ENSURE study also explored the combination of elebsiran (BRII-835) with BRII-179, a therapeutic HBV vaccine containing Pre-S1, Pre-S2, and S antigens.

• This combination induced a significant modification of HBV-specific immune responses, characterized by the production of anti-HBs antibodies and an expansion of interleukin-2 (IL-2) producing helper T cells specific for Pre-S1/Pre-S2 antigens. Notably, anti-HBs antibody levels of ≥100 IU/L persisted in approximately 40% of participants for at least 32 weeks after the combined treatment. The neutralizing capacity of these anti-HBs positive sera was found to be associated with the degree of HBsAg reduction.[8]
• Interim Phase 2 data from Brii Bio indicated that the BRII-835 and BRII-179 combination induced stronger anti-HBs antibody responses and HBsAg-specific T-cell responses compared to either agent administered alone. In these combination cohorts, two participants achieved a maximum reduction in HBsAg to at or below the lower limit of quantification (LLOQ) by Week 40, accompanied by robust HBV-specific antibody and T-cell responses.[13]
• An intriguing finding from the ENSURE study was that participants who had previously mounted an anti-HBs response to BRII-179 achieved substantially higher rates of HBsAg seroclearance when subsequently treated with elebsiran plus PEG-IFNα. At Week 24 of this sequential therapy, 55.6% of BRII-179 responders achieved HBsAg seroclearance, compared to only 10.0% in those who were non-responders to the initial vaccine priming. This suggests that BRII-179 might serve as a tool to prime the immune system or identify patients who are more likely to benefit from subsequent HBsAg reduction and immunomodulation.[24]

7.2.3. With Monoclonal Antibody (Tobevibart / VIR-3434)

The MARCH study, led by Vir Biotechnology, evaluated the combination of VIR-2218 (elebsiran) with VIR-3434 (tobebevibart), an HBsAg-targeting monoclonal antibody.

• Early results showed that this combination led to HBsAg declines of 2.7-3.1 log10 IU/mL at the end of treatment.[41]
• Preliminary data from 24 weeks post-end of treatment in the MARCH study indicated that the combination of tobevibart and elebsiran, either without or with PEG-IFNα, resulted in HBsAg loss in 17% (3/18) and 21% (3/14) of participants, respectively, who had low baseline HBsAg levels (<1000 IU/mL). In this subgroup, functional cure rates (sustained HBsAg loss and undetectable HBV DNA off NRTIs) were 11% (2/18) and 15% (2/13), respectively. When considering all participants regardless of baseline HBsAg, the HBsAg loss rates were 8% (4/51) and 16% (5/32) for the two-drug and three-drug combinations, respectively.[20]
• Preclinical data and early clinical observations also suggested that the combination of VIR-2218 and VIR-3434 resulted in greater reductions in HBsAg and HBV DNA levels compared to VIR-2218 monotherapy.[11]

7.3. Durability of Response and Predictors

A critical aspect of evaluating new CHB therapies is the durability of the response after treatment cessation. Sustained HBsAg seroclearance at 24 weeks post-EOT has been a key secondary endpoint in many of these trials. This was achieved in a subset of patients, particularly those receiving VIR-2218 in combination with PEG-IFNα.[19]

Several factors have emerged as potential predictors of a favorable and sustained response:

• Anti-HBs Titers: In the VIR-2218 plus PEG-IFNα study (NCT03672188), the development of anti-HBs seroconversion with antibody titers >500 mIU/mL at the end of treatment was found to be predictive of a sustained response (HBsAg seroclearance) at 24 weeks post-EOT.[19]
• Baseline HBsAg Levels: Lower baseline HBsAg levels (e.g., <1000 IU/mL or <1500 IU/mL) appear to be associated with higher rates of HBsAg loss or seroclearance when treated with combination therapies involving ALN-HBV-02.[20] This suggests that patients with a lower burden of HBsAg may be more amenable to achieving functional cure.

The collective clinical efficacy data for ALN-HBV-02 in CHB strongly support the necessity of combination therapy to achieve meaningful rates of functional cure. While ALN-HBV-02 monotherapy effectively reduces HBsAg levels, the rates of sustained HBsAg loss and seroconversion are low.[8] This is likely because chronic HBV infection involves profound and multifaceted immune exhaustion, and merely reducing the viral antigen load with an siRNA may not be sufficient to spontaneously restore effective host immune control in the majority of patients.[8] The virus's persistence, particularly due to the stability of covalently closed circular DNA (cccDNA) in infected hepatocytes, further complicates eradication efforts.

Combination strategies aim to address these challenges through synergistic mechanisms. For instance, pairing siRNA-mediated HBsAg reduction with PEG-IFNα is thought to make hepatocytes less immunosuppressive and more responsive to IFN's broad immunomodulatory and direct antiviral effects, thereby boosting both innate and adaptive immune responses.[19] Similarly, lowering HBsAg levels with an siRNA may "unmask" the immune system, allowing therapeutic vaccines like BRII-179 to more effectively stimulate HBV-specific T-cell and B-cell responses, leading to active immune control.[8] The combination of siRNA with an HBsAg-targeting monoclonal antibody like tobevibart offers another approach: the siRNA reduces the production of new HBsAg, while the mAb can neutralize existing circulating HBsAg and potentially mediate the clearance of infected cells through Fc-dependent effector functions.[11] Clinical trial results consistently demonstrate higher rates of HBsAg seroclearance and seroconversion with these combination regimens compared to historical data for monotherapies or even ALN-HBV-02 monotherapy within the same trial frameworks.[19] This evolving understanding strongly suggests that the path towards a functional cure for CHB with ALN-HBV-02 lies in its judicious use as a component of multi-targeted regimens, likely tailored to specific patient subpopulations based on baseline viral and immune characteristics.

8. Clinical Efficacy in Chronic Hepatitis D (Emerging Data)

8.1. Rationale for Targeting HDV via HBsAg Reduction

Chronic hepatitis D virus (HDV) infection is contingent upon a concurrent HBV infection. HDV is a satellite virus that utilizes the HBsAg produced by HBV as its envelope protein, which is essential for HDV assembly, maturation, and entry into new hepatocytes.[3] Consequently, therapeutic strategies that effectively reduce the production and availability of HBsAg, such as treatment with elebsiran, are mechanistically poised to inhibit the HDV lifecycle by depriving it of this critical component.

8.2. Combination with Tobevibart (VIR-3434)

In the context of HDV, elebsiran (VIR-2218) is primarily being investigated in combination with tobevibart (VIR-3434), an investigational monoclonal antibody that specifically targets HBsAg. This combination strategy offers a dual mechanism of action: elebsiran works intracellularly to suppress the production of new HBsAg by degrading HBV mRNA, while tobevibart acts extracellularly to neutralize existing circulating HBsAg and HDV virions (which are enveloped by HBsAg) and may also facilitate the clearance of infected cells.[3]

8.3. SOLSTICE Phase 2 Study (NCT05461170)

The SOLSTICE study is an ongoing, global Phase 2 clinical trial designed to evaluate the efficacy, safety, and tolerability of tobevibart and elebsiran, administered either alone or in combination, in participants with chronic HDV infection. The study includes patients with compensated cirrhosis, reflecting the often severe nature of CHD.[4]

Key findings from the SOLSTICE study include:

• At Week 24, in the cohort receiving tobevibart plus elebsiran every 4 weeks (Q4W) de novo, 41% of participants achieved HDV RNA Target Not Detected (TND). Furthermore, 100% of participants in this cohort achieved either an HDV RNA reduction of ≥2 log10 IU/mL or HDV RNA levels below the LLOQ.[26]
• Alanine aminotransferase (ALT) normalization was observed in 47% of participants in this combination cohort at Week 24.[26]
• Importantly, high rates of HDV RNA TND at Week 24 were observed in the combination arm regardless of baseline cirrhotic status, baseline HDV viremia levels, or baseline HBsAg levels, suggesting broad applicability across different patient profiles within the CHD population.[26]
• Earlier, more limited data from a small subset of six participants in the SOLSTICE trial showed that after 12 weeks of combination treatment with tobevibart and elebsiran, five out of six participants achieved undetectable HDV RNA, and all six were below the LLOQ.[28]

8.4. ECLIPSE Phase 3 Registrational Program

Based on the encouraging results from the Phase 2 SOLSTICE study, Vir Biotechnology has initiated the ECLIPSE global Phase 3 registrational program. This program is designed to definitively evaluate the efficacy and safety of the tobevibart and elebsiran combination therapy for the treatment of CHD.[2] The ECLIPSE program consists of three distinct trials:

• ECLIPSE 1 (NCT number not specified, but part of the program): This trial will compare the combination therapy to deferred treatment in regions where bulevirtide (an approved HDV entry inhibitor in some territories) is not available or access is limited. The composite primary endpoint is HDV RNA TND and ALT normalization at Week 48.[27] This trial plans to enroll 120 participants.
• ECLIPSE 2: This trial will evaluate the efficacy and safety of switching to the tobevibart and elebsiran combination in individuals with CHD who have not achieved viral suppression with prior bulevirtide therapy.[27]
• ECLIPSE 3: This is a Phase 2b head-to-head trial designed to compare tobevibart and elebsiran against bulevirtide in bulevirtide-naïve patients. This study aims to provide important supportive data for access and reimbursement in key markets.[27]

The ECLIPSE program plans for long-term treatment, potentially up to 240 weeks (5 years), to assess sustained virologic response, long-term safety, and the impact on clinical outcomes such as the development of end-stage liver disease.[30] The first patient was enrolled in the ECLIPSE program in March 2025.[2]

The rapid advancement of the elebsiran and tobevibart combination into Phase 3 trials for CHD signifies its substantial potential to address a critical unmet medical need. CHD is the most aggressive form of viral hepatitis, often leading to rapid progression to cirrhosis, liver failure, and hepatocellular carcinoma, with very few effective and well-tolerated treatment options currently available.[3] The existing approved therapy, bulevirtide, is not universally available, and response rates can vary. The complementary mechanisms of action of elebsiran (reducing HBsAg production) and tobevibart (neutralizing existing HBsAg and HDV virions, potentially clearing infected cells) provide a strong rationale for their combined use.[3] The high rates of HDV RNA suppression observed in Phase 2, such as 41% achieving HDV RNA TND at Week 24 in the SOLSTICE study [26], and even more profound responses in smaller initial cohorts [28], are highly promising and likely surpass what is typically achieved with current standards of care. The granting of FDA Breakthrough Therapy and Fast Track designations, alongside EMA PRIME status, further underscores the perceived potential of this combination therapy and serves to facilitate its expedited development and review.[27] If the Phase 3 ECLIPSE trials confirm the efficacy and safety profile observed in earlier studies, the combination of elebsiran and tobevibart could emerge as a new standard of care for CHD, potentially offering a functional cure or sustained virologic control for a significantly larger proportion of patients than is currently achievable. This would represent a major therapeutic advance for individuals suffering from this devastating liver disease.

9. Safety and Tolerability Profile

9.1. Overall Safety in Healthy Volunteers (Single Doses of VIR-2218)

The initial safety assessment of VIR-2218 (elebsiran) was conducted in healthy volunteers as part of the Phase 1 study NCT03672188 (Part A). In this population, single subcutaneous doses of VIR-2218 ranging from 50 mg to 900 mg were found to be well-tolerated.[17] No severe or serious adverse events (SAEs) were reported, and no participants discontinued the study due to adverse events within this dose range.[17] This safety profile was notably improved compared to its precursor, ALN-HBV (which lacked the ESC+ modifications), as ALN-HBV had been associated with dose-dependent ALT elevations in earlier studies.[5] The incorporation of ESC+ technology in VIR-2218 was specifically designed to mitigate such off-target effects and indeed demonstrated a substantially decreased propensity to cause ALT elevations in healthy volunteers at clinically relevant doses.[18]

9.2. Safety in CHB Patients (VIR-2218 Monotherapy)

In CHB patients receiving VIR-2218 monotherapy (200 mg every 4 weeks for six doses) in Cohort 1 of the NCT03672188 study, treatment-emergent adverse events (TEAEs) assessed as related to VIR-2218 were reported in 3 out of 15 participants (20%). The majority of these TEAEs were of Grade 1 or Grade 2 severity.[19] Alanine aminotransferase (ALT) elevations occurred in 2 out of 15 (13%) participants in this monotherapy arm.[19] Early studies of VIR-2218 monotherapy did not report any SAEs related to the drug.[38]

9.3. Safety in CHB Patients (VIR-2218 in Combination with PEG-IFNα)

When VIR-2218 was combined with PEG-IFNα in CHB patients (NCT03672188, Cohorts 2-6; ENSURE study):

• The frequency of TEAEs attributed to VIR-2218 ranged from 27% to 46% across the various combination cohorts in NCT03672188.[19]
• TEAEs related to PEG-IFNα were common, reported in 60% to 100% of participants across these cohorts, which is consistent with the well-established side effect profile of PEG-IFNα.[19]
• ALT elevations were notably more frequent in patients receiving combination therapy (ranging from 60% to 94% across cohorts) compared to those on VIR-2218 monotherapy (13%).[19] These elevations were generally Grade 1-2 and were often considered by investigators to be related to the immunomodulatory effects of PEG-IFNα or part of a favorable immune response leading to clearance of infected cells.
• Overall, the combination of VIR-2218 and PEG-IFNα was reported as generally well-tolerated. Most adverse events were mild to moderate in severity and were largely consistent with the known adverse effects of PEG-IFNα therapy.[29] Similar findings were reported in the ENSURE study, where the incidence of TEAEs was comparable between the elebsiran plus PEG-IFNα combination cohorts and the PEG-IFNα alone cohort.[34]

9.4. Safety in CHB Patients (VIR-2218 in Combination with BRII-179 Vaccine)

In a Phase 2 study conducted by Brii Biosciences, the combination of BRII-835 (elebsiran) and the therapeutic vaccine BRII-179 was reported to be generally safe and well-tolerated. No new safety signals emerged beyond those observed in previous single-agent studies of the respective compounds.[13]

9.5. Safety in CHB Patients (VIR-2218 in Combination with Tobevibart mAb)

Data from the MARCH study, which evaluated VIR-2218 (elebsiran) in combination with tobevibart (VIR-3434), with or without PEG-IFNα, indicated that these combinations were generally well-tolerated. Adverse events were primarily mild, and in some reports, all treatment-related AEs were Grade 1, with no study discontinuations due to AEs.[41] The safety profile was described as consistent with prior studies, with TEAEs being generally mild or moderate in nature.[20]

9.6. Safety in CHD Patients (Elebsiran in Combination with Tobevibart mAb)

In the SOLSTICE Phase 2 study for chronic hepatitis D, the combination of tobevibart and elebsiran was also reported to be generally well-tolerated.[26] While specific AE frequencies for the HDV indication are still emerging from ongoing trials, the safety profile observed in HBV patients with this combination [13] provides an initial basis for expectations in the HDV population.

9.7. Specific Adverse Events of Note

• ALT Elevations: As highlighted, ALT elevations were more common when VIR-2218 was used in combination with PEG-IFNα. In the NCT03672188 study, these were predominantly Grade 1-2.[19] Clinical trial protocols typically include specific guidelines for monitoring and managing ALT elevations.[44]
• Injection Site Reactions: Being a subcutaneously administered therapy, injection site reactions (such as pain, redness, or swelling) are potential adverse events, generally expected to be mild to moderate.[45]
• Flu-like Symptoms: When combined with PEG-IFNα, patients commonly experienced flu-like symptoms such as headache, fatigue, and malaise, which are well-recognized side effects of interferon therapy.[45]

9.8. General Safety Monitoring in Clinical Trials

Standard safety monitoring in ALN-HBV-02 clinical trials involves regular clinical assessments, including vital signs and physical examinations. Comprehensive laboratory tests are performed, covering hematology, serum chemistry (with a particular focus on liver function tests such as ALT, AST, bilirubin, and alkaline phosphatase), and urinalysis.[12] All adverse events are meticulously recorded, graded for severity (commonly using scales like Common Terminology Criteria for Adverse Events, CTCAE, Grades 1-4), and assessed by investigators for their potential relatedness to the study drug(s).[44] Independent Safety Review Committees (SRCs) or Data Safety Monitoring Boards (DSMBs) are typically employed to perform ongoing reviews of cumulative safety and tolerability data to ensure patient safety throughout the trial.[16]

9.9. Contraindications

Specific contraindications for ALN-HBV-02 as a marketed product are not yet defined, as it remains investigational. However, contraindications for participation in its clinical trials can be inferred from typical exclusion criteria. These often include known hypersensitivity to the investigational product or its excipients, pregnancy or breastfeeding, significant uncontrolled comorbidities (e.g., severe cardiac, renal, or pulmonary disease), presence of other active liver diseases (e.g., autoimmune hepatitis, alcoholic liver disease), decompensated cirrhosis (in many initial CHB studies), active malignancy, and use of certain prohibited concomitant medications.[16] General biosafety guidelines for handling investigational agents are also applicable but do not list drug-specific contraindications.[46]

The safety data gathered to date suggest that ALN-HBV-02, particularly with its ESC+ chemistry, possesses a generally favorable safety profile when administered as monotherapy, with a relatively low incidence of adverse events and ALT elevations.[17] When used in combination therapies, the overall adverse event profile tends to be influenced significantly by the known side effects of the partner drug, most notably PEG-IFNα, which is associated with a higher burden of AEs like flu-like symptoms and cytopenias.[19] The increased frequency of ALT elevations in IFN-containing regimens is also largely attributed to the immunomodulatory activity of IFN. A critical aspect of ongoing and future research is to determine whether these combinations lead to unexpected or synergistic toxicities beyond what is known for the individual components. Current evidence largely suggests that the AE profiles are additive rather than synergistic in a detrimental way. The decision to employ combination therapy involves a careful benefit-risk assessment: the potential for increased efficacy (e.g., higher rates of HBsAg seroclearance and functional cure) must be weighed against the potential for an increased, albeit generally manageable, adverse event burden. For a chronic condition like HBV, where the goal is a finite curative regimen, patients and clinicians may be willing to accept a temporarily higher side effect profile compared to indefinite NUC therapy, which typically has minimal side effects but offers no prospect of cure. The development of ALN-HBV-02 will likely continue to focus on identifying combination partners that not only maximize antiviral and immunological efficacy but also maintain an acceptable overall safety and tolerability profile suitable for the target patient populations. The relatively good tolerability reported for the elebsiran plus tobevibart combination, which does not include interferon, is an encouraging sign in this regard.[20]

10. Regulatory Status and Designations

ALN-HBV-02 (elebsiran), particularly when investigated in combination with tobevibart (VIR-3434) for the treatment of chronic hepatitis D (CHD), has received several expedited regulatory designations from major health authorities. These include:

• Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA).[2] This designation is intended to expedite the development and review of drugs that are intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
• Fast Track Designation from the U.S. FDA.[2] Fast Track designation is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
• Priority Medicines (PRIME) Designation from the European Medicines Agency (EMA).[27] The PRIME scheme offers enhanced support to medicines that target an unmet medical need, including early dialogue and scientific advice to help optimize development plans and speed up assessment of marketing authorization applications.
• Orphan Drug Status: While not explicitly stated for ALN-HBV-02 alone, therapies for HDV often qualify for Orphan Drug Designation due to the relative rarity of the condition compared to HBV monoinfection. Such a designation provides incentives to support development for rare diseases.[6]

Furthermore, in the context of chronic HBV infection, BRII-835 (elebsiran) in combination with BRII-877 (tobebevibart) received Breakthrough Therapy Designations from the National Medical Products Administration (NMPA) in China. This was based on Phase 1 and 2 clinical studies conducted by Brii Biosciences and its partner Vir Biotechnology.[14]

These various designations are highly significant. They reflect a recognition by regulatory authorities of the serious nature of CHB and particularly CHD, the substantial unmet medical need for effective treatments, and the promising preliminary clinical data generated by ALN-HBV-02-containing regimens. The benefits conferred by these designations, such as more frequent interactions with regulatory agencies, eligibility for rolling review of marketing applications, and the potential for accelerated approval pathways, can substantially shorten the time it takes for a promising new therapy to reach patients.

The accumulation of these expedited regulatory statuses, especially for the elebsiran and tobevibart combination in CHD, strongly indicates that regulatory bodies perceive this therapeutic approach as having the potential to offer a significant clinical advantage over available options, or where no satisfactory options exist. The severity of HDV, characterized by its rapid progression to cirrhosis and liver cancer and the paucity of effective treatments [3], makes it a prime candidate for such accelerated programs. The compelling early efficacy data from studies like SOLSTICE, demonstrating marked HDV RNA reduction [26], coupled with a rational, dual mechanism of action, likely contributed significantly to these regulatory recognitions. This active engagement and support from regulatory agencies are positive prognostic indicators for the overall development trajectory of ALN-HBV-02, particularly in the HDV space, and also highlight its potential within combination strategies for HBV in regions like China where the disease burden is immense.

11. Discussion: Current Standing and Future Directions

ALN-HBV-02 (elebsiran/VIR-2218/BRII-835) has emerged as a significant investigational agent in the evolving landscape of therapies for chronic viral hepatitis. Its core strength lies in its potent and generally sustained ability to reduce HBsAg levels, a key viral protein implicated in HBV persistence, immune evasion, and liver pathogenesis.[5] The incorporation of Enhanced Stabilization Chemistry Plus (ESC+) technology has been pivotal, conferring an improved hepatic safety profile compared to earlier generation RNAi candidates, thereby enhancing its therapeutic potential.[5]

11.1. The Imperative of Combination Therapy for Functional Cure in CHB

Clinical evidence to date strongly indicates that while ALN-HBV-02 monotherapy can achieve substantial HBsAg knockdown, it is generally insufficient to induce high rates of functional cure (defined as sustained HBsAg loss, with or without anti-HBs seroconversion, and undetectable HBV DNA off-treatment) in the majority of CHB patients.[8] The chronicity of HBV infection is maintained by a complex interplay of factors, including the extreme stability of the viral cccDNA reservoir in infected hepatocytes and profound, multifaceted dysregulation of the host immune system.[5] Addressing these deep-seated mechanisms typically requires more than just viral protein suppression.

Consequently, the development strategy for ALN-HBV-02 in CHB has increasingly focused on its role as a foundational component within combination regimens. Pairing ALN-HBV-02 with immunomodulatory agents, such as PEG-IFNα or therapeutic vaccines (e.g., BRII-179), aims to simultaneously reduce the suppressive HBsAg load and actively stimulate or restore host antiviral immune responses. Similarly, combining it with other direct-acting antiviral agents, notably HBsAg-targeting monoclonal antibodies like tobevibart, offers a multi-pronged attack on the virus. Clinical trials have consistently demonstrated that these combination approaches yield significantly improved virological and serological outcomes, including higher rates of HBsAg seroclearance and anti-HBs seroconversion, compared to what is achievable with monotherapy.[8]

11.2. Promise in HDV: A More Direct Path to Clinical Impact?

The application of ALN-HBV-02 in chronic hepatitis D (CHD) has shown particular promise. Given that HDV is entirely dependent on HBV-supplied HBsAg for its replication and virion assembly, the HBsAg-lowering effect of elebsiran, especially when combined with the HBsAg-neutralizing activity of tobevibart, provides a highly rational and potent therapeutic strategy.[3] The rapid progression of this combination into the Phase 3 ECLIPSE registrational program, supported by multiple expedited regulatory designations (FDA Breakthrough Therapy, Fast Track; EMA PRIME), underscores the significant unmet need in CHD and the potential of this regimen to become a new standard of care.[2] The robust HDV RNA suppression observed in Phase 2 studies suggests a potentially more straightforward path to demonstrating clinical benefit in CHD compared to the complexities of achieving functional cure in CHB.

11.3. Challenges and Unanswered Questions

Despite the progress, several challenges and questions remain in the development and future application of ALN-HBV-02:

• Optimal Combination Regimens for CHB: Identifying the most effective and well-tolerated combination partners, along with optimal dosing schedules and treatment durations for diverse CHB patient populations (e.g., varying HBeAg status, baseline HBsAg levels, viral genotypes, degrees of liver fibrosis, prior treatment history), remains a key area of investigation.[21]
• Durability of Response: Long-term follow-up data from ongoing and future trials will be crucial to ascertain the true durability of HBsAg loss and functional cure after the cessation of all therapies.
• Impact on HBV cccDNA: While HBsAg reduction is a primary endpoint, the direct and indirect effects of ALN-HBV-02-based therapies on the stability, transcriptional activity, and potential depletion of the HBV cccDNA reservoir require further elucidation. Some evidence suggests that significant HBsAg reduction might indirectly lead to a decline in cccDNA activity by alleviating HBsAg-mediated immune suppression.[5]
• Patient Selection and Biomarkers: The development of reliable biomarkers to predict treatment response and guide patient selection is critical. Factors such as baseline HBsAg levels [20], on-treatment anti-HBs antibody titers [19], or prior immune responses to agents like therapeutic vaccines [34] may help tailor therapies to individuals most likely to benefit.
• Global Accessibility and Cost-Effectiveness: Should ALN-HBV-02-based regimens prove successful, ensuring their affordability and accessibility, particularly in regions with a high burden of HBV and HDV, will be a significant public health challenge that requires careful consideration.[21]

11.4. Future Research Directions

Future research involving ALN-HBV-02 will likely focus on:

• Continued exploration of novel combination partners, potentially including next-generation immunomodulators, capsid assembly modulators, cccDNA-targeting agents, or other RNA-based therapeutics.
• Optimization of finite treatment durations aimed at achieving sustained off-treatment virologic and immunologic control.
• Long-term studies to evaluate the clinical benefits of HBsAg reduction and functional cure on hard outcomes such as liver fibrosis regression, prevention of cirrhosis, and reduction in HCC incidence.
• Further refinement of patient stratification strategies based on predictive biomarkers.
• Assessment of efficacy and safety in special populations, such as those with cirrhosis or co-infections.

Vir Biotechnology and its partners, Alnylam and Brii Biosciences, are expected to report additional clinical data from multiple ongoing Phase 2 studies of ALN-HBV-02 (VIR-2218/elebsiran/BRII-835) throughout 2024 and beyond.[14] The SOLSTICE and particularly the ECLIPSE trials will provide pivotal data regarding its role in CHD management. These ongoing efforts will be crucial in defining the ultimate place of ALN-HBV-02 in the therapeutic armamentarium against chronic hepatitis B and D.

12. Conclusion

ALN-HBV-02 (elebsiran/VIR-2218/BRII-835) represents a significant advancement in the field of RNAi therapeutics for viral hepatitis. Its mechanism of action, targeting HBV mRNA to potently reduce HBsAg and other viral proteins, combined with the enhanced hepatic safety profile afforded by ESC+ technology, has established it as a promising agent. While monotherapy effectively lowers HBsAg, the path to achieving high rates of functional cure in chronic hepatitis B necessitates its use within combination regimens that also address host immune dysfunction. Numerous studies pairing ALN-HBV-02 with immunomodulators like PEG-IFNα, therapeutic vaccines, or HBsAg-targeting monoclonal antibodies have demonstrated improved serological outcomes and are paving the way towards finite, curative treatment strategies.

For chronic hepatitis D, the combination of elebsiran with the monoclonal antibody tobevibart has shown particularly strong promise, rapidly progressing to Phase 3 trials and garnering multiple expedited regulatory designations due to the high unmet medical need and compelling early efficacy data. This positions the combination as a potential new standard of care for this severe form of liver disease.

Despite the considerable progress, challenges remain, including the optimization of combination regimens for diverse patient populations, ensuring long-term durability of response, and addressing global accessibility. Ongoing and future clinical trials will be critical in further defining the efficacy, safety, and ultimate role of ALN-HBV-02-based therapies. Nevertheless, ALN-HBV-02 stands as a testament to the potential of RNAi technology and innovative drug design to tackle complex chronic viral infections, offering renewed hope for patients with chronic hepatitis B and D.

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