AL-034 (JNJ-64794964 / TQ-A3334): A Comprehensive Profile of an Investigational Toll-like Receptor 7 Agonist

Executive Summary

AL-034 is an orally bioavailable, investigational small molecule therapeutic agent identified as a selective agonist of Toll-like Receptor 7 (TLR7). This positions the compound as a potent immunomodulator designed to harness the body's innate and adaptive immune systems to combat disease. Its primary therapeutic indication is the treatment of Chronic Hepatitis B (CHB) viral infection, a condition with a significant global health burden and a high unmet need for curative therapies. The overarching goal in this indication is to achieve a "functional cure," defined by sustained loss of hepatitis B surface antigen (HBsAg) and undetectable viral DNA after a finite course of treatment. The drug was also investigated for a secondary indication in advanced Non-Small Cell Lung Cancer (NSCLC), leveraging the same immune-activating mechanism, though this line of development has since been discontinued.

The mechanism of action of AL-034 is centered on its ability to bind to and activate endosomal TLR7, mimicking the natural recognition of single-stranded viral RNA. This activation initiates a robust downstream signaling cascade, leading to the production of Type I interferons (IFN-α) and a broad array of pro-inflammatory cytokines and chemokines. This, in turn, stimulates a multifaceted immune response involving the activation of natural killer (NK) cells, dendritic cells, macrophages, and B cells, ultimately priming a potent, antigen-specific CD8+ T-cell response. Preclinical studies in a murine model of CHB demonstrated remarkable, dose-dependent antiviral activity, including rapid and sustained clearance of both HBV-DNA and HBsAg. A key finding from these studies was that viral clearance was achieved via a non-cytolytic, cytokine-mediated mechanism, suggesting a potential for high efficacy without the hepatotoxicity often associated with immune-mediated liver flares.

Clinically, AL-034 has progressed to Phase 2 development for CHB. Phase 1 studies in healthy volunteers established a predictable, on-target safety profile, characterized primarily by transient, mild-to-moderate flu-like symptoms (e.g., fever, headache, myalgia) and transient lymphopenia, consistent with IFN-α exposure. The compound's pharmacokinetic profile is characterized by rapid absorption under fasted conditions, but with a significant negative food effect that reduces bioavailability by more than 50%. Furthermore, sophisticated pharmacokinetic/pharmacodynamic modeling has revealed significant population-based variability in responsiveness, with female participants and individuals of Asian descent showing heightened sensitivity.

The strategic termination of the NSCLC program, coupled with the advancement of a well-designed Phase 2 combination therapy trial for CHB, indicates a focused corporate strategy prioritizing the virology indication. The future of AL-034 hinges on its ability to translate the profound efficacy seen in preclinical models into meaningful and durable HBsAg reduction in human patients at a tolerable dose. Its potential as a cornerstone of a curative combination regimen for CHB is substantial, but it must overcome the historical challenges of efficacy and tolerability that have faced the TLR7 agonist class. The ongoing clinical trials are therefore a critical inflection point for determining the ultimate therapeutic value of this promising immunomodulatory agent.

Drug Identification and Development History

Nomenclature and Identifiers

The investigational agent AL-034 is a small molecule that has been developed under a complex network of corporate partnerships, resulting in the use of multiple synonyms and development codes across different organizations and stages of research. A comprehensive understanding of its identity requires familiarity with this complete nomenclature. The compound is most frequently referred to by the following identifiers:

• Primary Names: AL-034, AL 034 [1]
• Development Codes: JNJ-4964, JNJ-64794964 (associated with Janssen/Johnson & Johnson) [1]
• Development Code: TQ-A3334 (associated with Chia Tai Tianqing Pharmaceutical Group) [1]

For cataloging and database tracking purposes, it is assigned the DrugBank Accession Number DB17471.[1]

Classification

AL-034 is systematically classified based on its molecular and therapeutic properties:

• Modality: It is a Small Molecule drug, distinguishing it from biologic therapies like monoclonal antibodies or therapeutic vaccines.[1]
• Therapeutic Class: Based on its mechanism and intended applications, it falls under several therapeutic classes, including Antivirals, Immunotherapies, and Antineoplastics.[5] This dual classification as both an antiviral and an antineoplastic agent is not a result of repurposing but is a direct reflection of its core immunomodulatory mechanism. The stimulation of T-cell-mediated immunity via TLR7 agonism is a foundational principle in the modern therapeutic approaches to both chronic viral infections and oncology. The drug's development history, which includes clinical trials in both domains, underscores this inherent mechanistic duality.
• Regulatory Status: The drug is currently Investigational and has not received regulatory approval for any indication in any market.[1] It has been designated as a New Molecular Entity (NME), signifying that its active moiety has not been previously approved by a national regulatory authority.[5]

Corporate Development Pathway

The development history of AL-034 is notable for its involvement of multiple international pharmaceutical and biotechnology companies, indicating a strategic, collaborative, or licensed program. The key entities involved are:

• Originator/Developer: Chia Tai Tianqing Pharmaceutical Group Co. Ltd., a major Chinese pharmaceutical company headquartered in Nanjing.[4]
• Developer: Alios BioPharma, Inc., a U.S.-based biotechnology company focused on antiviral therapies, which was later acquired by Johnson & Johnson.[4]
• Involved Parties: Janssen Research & Development (the pharmaceutical arm of Johnson & Johnson) and WuXi AppTec (a global contract research organization) have also been prominently involved in the research and development process.[4]

This intricate web of corporate involvement suggests a development pathway that likely began with initial discovery and preclinical work at Chia Tai Tianqing and/or Alios BioPharma. The subsequent involvement of a global pharmaceutical leader like Janssen/Johnson & Johnson points to the asset being sufficiently de-risked and validated at an early stage to warrant significant investment, acquisition, or a major licensing agreement. This multi-stakeholder validation from entities in both Asia and the West enhances the perceived potential of the drug. The global nature of the program is further reflected in the geographic distribution of its clinical trials, with studies being conducted in China, New Zealand, and other international locations, likely leveraging regional expertise in areas with high CHB prevalence alongside global pharmaceutical development infrastructure.[2]

Data Gaps: Chemical Structure and Synthesis

Despite a thorough review of publicly available scientific literature, clinical trial registries, and drug databases, the precise chemical structure, molecular formula, and synthesis pathway for AL-034 and its synonyms (JNJ-64794964, TQ-A3334) have not been disclosed.[1] This lack of structural information is common for investigational compounds where intellectual property is being closely guarded. It represents a significant gap in the public domain knowledge, precluding independent computational analysis, structure-activity relationship (SAR) assessment, or exploration of alternative synthesis routes by outside parties.

Intellectual Property Landscape

While the specific composition of matter patent for AL-034 is not explicitly identified, the intellectual property landscape appears to be robustly protected, primarily by its originating company. Public patent databases show multiple patents assigned to Chia Tai Tianqing Pharmaceutical Group Co., Ltd. related to TLR7 agonists. These patents cover not only specific chemical matter but also pharmaceutical compositions and methods of use, including drug combinations.[17] For instance, patent US12357637 covers a solid pharmaceutical composition of a TLR7 agonist, and patent US12336996 covers a drug combination containing a TLR7 agonist and entecavir for the treatment of HBV infection.[21] This suggests that Chia Tai Tianqing holds the core intellectual property for this molecule or a closely related class of molecules, which would form the basis for any partnership or licensing agreements with entities like Janssen. One database indicates an association with as many as 100 medical patents, reflecting a broad and deep intellectual property portfolio surrounding the asset.[2]

Mechanism of Action and Pharmacodynamics

The therapeutic potential of AL-034 is derived entirely from its function as a potent and selective immunomodulator. Its mechanism of action involves the targeted activation of a key receptor in the innate immune system, which in turn orchestrates a broad and powerful adaptive immune response.

Molecular Target: Toll-like Receptor 7 (TLR7)

The specific molecular target of AL-034 is Toll-like Receptor 7 (TLR7).[2] TLR7 is a member of the Toll-like receptor family of proteins, which serve as foundational pattern recognition receptors (PRRs) of the innate immune system. Unlike TLRs that are located on the cell surface, TLR7 is situated within the endosomal compartment of various immune cells, most notably plasmacytoid dendritic cells (pDCs) and B-lymphocytes.[22] Its natural function is to detect the presence of pathogens by recognizing specific pathogen-associated molecular patterns (PAMPs). For TLR7, the primary natural ligand is single-stranded viral RNA (ssRNA).[22] Upon recognition of its ligand, TLR7 acts as a critical sensor, initiating an immediate antiviral defense program and serving as a crucial link that bridges the initial innate immune response with the subsequent, more specific adaptive immune response.[2]

Pharmacological Action: Selective TLR7 Agonism

AL-034 is an orally bioavailable small molecule that functions as a direct agonist of TLR7.[2] This means it binds to and activates the TLR7 receptor, effectively mimicking the presence of viral ssRNA and triggering the same downstream signaling cascade that would occur during a natural viral infection. In vitro studies have characterized it as a potent and selective TLR7 agonist.[26] This selectivity is important, as related receptors like TLR8 have different expression patterns and can induce a distinct, more pro-inflammatory cytokine profile that may be less desirable for therapeutic applications in chronic viral hepatitis.[24]

Immunomodulatory Cascade

The activation of TLR7 by AL-034 initiates a well-defined, multi-step immunomodulatory cascade:

1. Innate Immune Activation and Cytokine Production: Upon binding of AL-034, TLR7 triggers an intracellular signaling pathway that is dependent on the adaptor protein MyD88.[23] This signaling converges on the activation of key transcription factors, including Interferon Regulatory Factor 7 (IRF7) and Nuclear Factor kappa B (NF- κB). This leads to the robust transcription and secretion of a host of immune-signaling molecules, most critically Type I Interferons (IFN-α), as well as a wide array of pro-inflammatory and anti-inflammatory cytokines and chemokines.[3]
2. Broad-Spectrum Cellular Activation: The resulting cytokine milieu acts as a powerful alarm system that activates a diverse set of immune cells. This includes the direct activation and enhancement of the effector functions of natural killer (NK) cells and macrophages, which are key players in the innate antiviral response.[3] It also promotes the maturation and activation of dendritic cells (DCs), the most potent antigen-presenting cells (APCs) in the body.[24]
3. Adaptive Immune Priming and T-Cell Response: The activation of DCs is the critical step that links the innate response to the adaptive immune system. Mature DCs process and present viral or tumor antigens to naive T-cells. The presence of Type I interferons and other co-stimulatory signals induced by AL-034 ensures the effective priming of a robust, antigen-specific adaptive immune response. This is characterized by the activation and clonal expansion of CD8+ cytotoxic T-lymphocytes (CTLs), which are capable of recognizing and eliminating infected cells or tumor cells, and CD4+ helper T-cells, which help coordinate the overall immune attack.[3]

This entire process represents a strategic therapeutic intervention designed to overcome the state of immune exhaustion or tolerance that characterizes chronic diseases like CHB.[22] Instead of merely suppressing the pathogen, AL-034 aims to function as an "immune restorative" agent, re-educating and re-invigorating the host's own immune system to establish long-term, durable control over the disease.

Pharmacodynamic (PD) Profile in Humans

Clinical studies in healthy volunteers have confirmed that oral administration of AL-034 produces the expected on-target pharmacodynamic effects, providing clear evidence of target engagement in humans.

• Biomarker Induction: A dose-dependent and transient increase in a panel of key immune biomarkers is consistently observed following administration. This induction confirms the activation of the TLR7-interferon pathway. Key induced biomarkers include:
• Interferon-Stimulated Genes (ISGs): Robust upregulation of the messenger RNA for genes like ISG15, MX1, and OAS1 in whole blood serves as a direct downstream signature of Type I interferon signaling.[6]
• Cytokines and Chemokines: Transient increases in the plasma concentrations of IFN-α, IP-10 (CXCL10), MCP-1, IL-1RA, and neopterin are observed.[6] CXCL10, in particular, is a critical chemokine involved in recruiting T-cells to sites of inflammation.
• Immune Cell Phenotyping and Transcriptomics: More sophisticated analyses have provided deeper insight into the cellular effects of AL-034.
• A single oral dose leads to a measurable increase in the frequency of activated NK cells (as defined by surface expression of markers like CD69, CD134, CD137, and/or CD253) and activated B cells (expressing CD86) in peripheral blood.[33]
• Transcriptomic analysis of peripheral blood cells revealed the upregulation of 59 distinct genes, predominantly ISGs, between 6 hours and 5 days after a single dose of the drug.[33]

These pharmacodynamic findings have also revealed a critical relationship between the level of immune activation and the drug's tolerability profile. The data indicate that NK cell activation correlates with levels of IFN-α induction that are associated with no or acceptable flu-like adverse events. In contrast, the more pronounced activation of B cells was predominantly observed at higher levels of IFN-α induction, which are associated with more significant flu-like symptoms.[33] This observation suggests the existence of a potential therapeutic window. The clinical development strategy must therefore focus not on maximizing TLR7 agonism, but on carefully titrating the dose to a level that achieves the desired therapeutic cellular response (e.g., NK and T-cell activation) while remaining below the threshold that causes intolerable systemic side effects driven by excessive cytokine release. This balance defines the drug's therapeutic index and represents a central challenge for the clinical development of AL-034 and the entire TLR7 agonist class.

Preclinical Efficacy and Safety

The rationale for advancing AL-034 into human clinical trials was built upon a strong foundation of preclinical data from relevant animal models, which demonstrated potent biological activity in both virology and oncology settings. These studies were crucial for establishing proof-of-concept, defining the mechanism of efficacy, and providing an initial assessment of the safety profile.

Chronic Hepatitis B Model (AAV/HBV Mice)

The primary preclinical evidence supporting the development of AL-034 for CHB comes from studies using the adeno-associated virus expressing HBV (AAV/HBV) mouse model. This model effectively mimics key aspects of chronic infection, including the persistent presence of viral DNA and antigens.

• Study Design and Efficacy: In a key study, AAV/HBV mice were treated with oral AL-034 (referred to as JNJ-4964) once-per-week for 12 weeks, followed by a 4-week treatment-free follow-up period to assess the durability of the response.[11] The results showed a clear dose-dependent antiviral effect:
• At a dose of 6 mg/kg, a partial decrease in plasma HBV-DNA and HBsAg was observed, with only a minimal immune response detected in a small fraction of animals.[11]
• At a higher dose of 20 mg/kg, the drug induced a rapid, profound, and complete suppression of viral markers. Both plasma HBV-DNA and HBsAg levels became undetectable in all treated animals within just three weeks of starting treatment.[11]
• Sustained Virologic Response: A critical finding was the durability of this response. Four weeks after the cessation of the 12-week treatment course, there was no rebound of plasma HBV-DNA or HBsAg levels in the high-dose group. This demonstrated the induction of a sustained virologic response (SVR), suggesting that the treatment had enabled the host immune system to establish long-term control of the virus, a key hallmark of a functional cure.[11]
• Immunological Correlates of Efficacy: The sustained antiviral effect was accompanied by the induction of a robust and specific anti-HBV immune response. High and sustained titers of anti-HBs antibodies were observed, which persisted through the treatment-free follow-up period. This humoral response was supported by the detection of HBsAg-specific immunoglobulin G (IgG)-producing B cells and interferon-gamma (IFN-γ)-producing CD4+ T cells in the spleen.[11] These findings confirm that AL-034 successfully re-engaged both the humoral and cellular arms of the adaptive immune system against the virus.
• Non-Cytolytic Mechanism of Viral Clearance: Perhaps the most significant finding from these preclinical studies was the mechanism by which viral clearance was achieved. Throughout the study, even at the highly efficacious 20 mg/kg dose, mice maintained normal levels of alanine aminotransferase (ALT), a key biomarker of liver injury. Histological examination of the liver at the end of treatment and after the follow-up period revealed no evidence of hepatocyte cell death and only minimal infiltration of B and T cells.[6] This strongly indicates that AL-034 induces viral clearance through a non-cytolytic, cytokine-mediated mechanism. This is a crucial differentiating feature. A major clinical challenge in developing immunotherapies for HBV is the risk of triggering severe liver flares, where a newly activated immune system attacks and destroys a large number of infected hepatocytes, leading to acute liver damage. The preclinical evidence for AL-034 suggests it may promote viral clearance primarily through intracellular, IFN-mediated processes that degrade viral components without killing the host cell. If this non-destructive clearance mechanism translates to human patients, it could represent a major safety and efficacy advantage, allowing for potent immune activation without the associated risk of severe hepatotoxicity.

Oncology Model (Syngeneic Murine Lung Cancer)

The immunomodulatory mechanism of AL-034 also provided a strong rationale for its investigation as a cancer therapeutic, particularly in combination with immune checkpoint inhibitors.

• Monotherapy and Combination Efficacy: In a syngeneic murine lung cancer model, oral administration of TQ-A3334 as a monotherapy demonstrated significant anti-tumor activity, effectively alleviating the tumor burden.[2] More importantly, when TQ-A3334 was combined with an anti-PD-L1 antibody (an immune checkpoint inhibitor), the combination therapy resulted in superior tumor control compared to either agent alone.[2]
• Immunological Mechanism of Anti-Tumor Activity: The anti-tumor effect was shown to be dependent on the induction of Type I Interferon. This IFN signaling led to the increased expression of the chemokine CXCL10 within the tumor tissue. CXCL10 is a potent chemoattractant for T-cells, and its upregulation resulted in the increased trafficking and abundance of CD8+ tumor-infiltrating lymphocytes (TILs) into the tumor microenvironment (TME).[2] The combination with anti-PD-L1 therapy led to a further increase in the frequency of these CD8+ TILs.[2]

This preclinical oncology data positions AL-034 not merely as an add-on therapy but as a mechanistic enabler of checkpoint blockade. Immune checkpoint inhibitors are most effective in "hot" tumors that are already infiltrated with T-cells, which can then be unleashed by blocking the PD-1/PD-L1 axis. They are often ineffective in immunologically "cold" tumors that lack T-cell infiltration.[2] The mechanism of AL-034 actively converts the TME from "cold" to "hot" by recruiting the necessary CD8+ T-cells. This suggests a powerful synergistic potential, where AL-034 primes the TME to make it susceptible to the effects of checkpoint inhibition, potentially broadening the patient population that could benefit from this class of cancer immunotherapy.

• Preclinical Safety: Across these studies, the drug was reported to exhibit low toxicity in animal models, supporting its advancement into human trials.[2]

Clinical Development Program

The clinical development of AL-034 has been pursued across two distinct therapeutic areas, virology and oncology, reflecting the broad applicability of its immunomodulatory mechanism. The program has included foundational Phase 1 studies in healthy volunteers to establish safety and pharmacology, followed by progression into patient populations. The trajectory of these programs reveals a clear strategic focus that has evolved over time.

A summary of the key clinical trials conducted for AL-034 and its synonyms is presented in Table 1.

Table 1: Summary of Key Clinical Trials for AL-034 (JNJ-64794964 / TQ-A3334)

ClinicalTrials.gov ID	Title	Phase	Status	Purpose	Indication(s)	Sponsor/Collaborator
NCT03285620	A Study of AL-034 to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses in Healthy Participants	1	Completed	Treatment	Viral Hepatitis B	Alios BioPharma, Inc.
NCT06160895	A Clinical Trial of TQ-A3334 Tablet After Multiple Administration in Adult Subjects	1	Completed	Treatment	Viral Hepatitis B	Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
NCT06706310	Evaluate TQ-A3334 Tablets Combined Nucleoside (Acid) Analogs in the Initial Treatment/Chronic Hepatitis B Virus (HBV) Infection Subjects of Chronic HBV Infection	2	Recruiting	Treatment	Chronic Hepatitis B	Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
NCT04273815	A Study of TQ-A3334 Monotherapy or Combined With Anlotinib or TQ-B2450 in Advanced Metastatic Non-small Cell Lung Cancer	1b/2	Terminated	Treatment	Non-Small Cell Lung Cancer (NSCLC)	Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
ChiCTR2300079331	Phase I Clinical Trial of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of TQ-A3334 Tablet in Healthy Adult Subjects	1	Suspended	Treatment	Healthy Volunteers	The First Hospital of Jilin University

(Data compiled from sources: [1])

Phase 1 Program in Healthy Volunteers

The clinical journey for AL-034 began with meticulously designed Phase 1 studies in healthy adult volunteers to establish its fundamental safety, tolerability, and pharmacokinetic/pharmacodynamic profile.

• NCT03285620: This was the first-in-human study, a double-blind, randomized, placebo-controlled trial sponsored by Alios BioPharma. It consisted of a single ascending dose (SAD) part, which also evaluated the effect of food on pharmacokinetics, and a multiple ascending dose (MAD) part.[27] The study was completed in November 2018, and results from the SAD portion were presented at The International Liver Congress™ (EASL) in 2019.[27]
• NCT06160895: This Phase 1 study, sponsored by Chia Tai Tianqing, further evaluated the safety and pharmacology of multiple doses of TQ-A3334 tablets in healthy adults. It was completed in August 2024.[2]

Collectively, these foundational studies were successful in their objectives. They established the initial safety profile of the drug, confirmed its on-target pharmacodynamic effects through biomarker analysis, and characterized key pharmacokinetic properties, including the significant food effect and population-based variability. The data generated from these trials provided the necessary evidence and confidence to advance the molecule into studies involving patient populations.

Chronic Hepatitis B (CHB) Program

The primary focus of the AL-034 development program is on Chronic Hepatitis B, a disease that affects nearly 300 million people worldwide and remains a leading cause of cirrhosis and liver cancer.[39] Current standard-of-care therapies, primarily nucleos(t)ide analogues (NAs), can effectively suppress viral replication but rarely lead to a cure due to the persistence of the viral reservoir, the covalently closed circular DNA (cccDNA), in infected hepatocytes.[39] The strategic goal for new CHB therapies like AL-034 is to achieve a "functional cure," defined as the sustained loss of HBsAg with or without seroconversion to anti-HBs antibodies after a finite duration of therapy.[39]

The CHB program for AL-034 has successfully advanced to Phase 2, its highest stage of development.[2]

• NCT06706310: This is the flagship ongoing trial for the program. It is a Phase 2, randomized, double-blind, placebo-controlled, multi-center study being conducted in China. The study is designed to evaluate the efficacy and safety of TQ-A3334 tablets administered in combination with standard-of-care NAs for the treatment of CHB.[2] The design of this trial is critically important, as it reflects the consensus strategy in the field that a functional cure will likely require a combination of direct viral suppression (from the NA) to reduce the viral and antigenic load, coupled with an immunomodulatory agent (like AL-034) to reinvigorate the host immune system to clear the remaining virus and establish long-term control.

Non-Small Cell Lung Cancer (NSCLC) Program

Leveraging the compelling preclinical data that showed T-cell infiltration into tumors and synergy with checkpoint inhibitors, a clinical program was initiated for AL-034 in NSCLC.

• NCT04273815: This was a Phase 1b/2 study designed to evaluate TQ-A3334 both as a monotherapy and in combination with the multi-kinase inhibitor anlotinib or a PD-L1 inhibitor in patients with advanced, metastatic NSCLC who had progressed on prior lines of chemotherapy.[1]
• Status: Terminated: This clinical trial was officially terminated.[1] The specific, official reason for the termination has not been disclosed in the available materials. Clinical trials can be terminated for a variety of reasons, including but not limited to concerns over safety, clear evidence of futility (lack of efficacy), slow patient accrual, or strategic/business decisions by the sponsor to reallocate resources.[45]

The concurrent termination of the NSCLC program and the confident advancement of the CHB program into a large Phase 2 combination study represents a clear and decisive strategic pivot. This pattern strongly suggests that either the emerging data from the NSCLC trial was disappointing—perhaps indicating a lack of efficacy or an unfavorable safety profile in this more complex and heavily pre-treated patient population—or that the data and prospects in CHB were so compelling that the company made a strategic decision to consolidate resources onto the program with the highest probability of success. While the lack of a publicly stated reason for the NSCLC trial termination casts uncertainty on the drug's future potential in oncology, it simultaneously reinforces the sponsor's apparent confidence in its primary indication, CHB.

Clinical Pharmacology: Pharmacokinetics (PK)

The study of pharmacokinetics (PK)—how the body absorbs, distributes, metabolizes, and excretes a drug—is fundamental to understanding its clinical behavior and optimizing its dosing regimen. For AL-034, clinical pharmacology studies in healthy volunteers have revealed several key characteristics that have significant implications for its development and potential therapeutic use.

Absorption

• Rate of Absorption: Following oral administration, AL-034 is absorbed rapidly. Under fasted conditions, the time to reach maximum plasma concentration (Tmax) is consistently observed to be very short, approximately 0.42 to 0.5 hours (25 to 30 minutes).[15] This rapid onset of absorption is a notable feature of the compound.
• Food Effect: The absorption of AL-034 is profoundly influenced by the presence of food. Co-administration of the drug with a meal results in a substantial reduction in its systemic exposure. A formal population PK analysis, which pooled data from multiple studies, quantified this effect precisely, determining that the relative bioavailability of AL-034 was only 44.2% in the fed state compared to the fasted state.[28] This means that taking the drug with food reduces the amount of drug that reaches the bloodstream by more than half. This is a clinically significant finding that necessitates strict dosing instructions—requiring administration on an empty stomach—to ensure consistent and adequate drug exposure in clinical trials and any future clinical practice.

Distribution, Metabolism, and Excretion (ADME)

Detailed public information on the distribution, metabolism, and excretion pathways of AL-034 is limited. However, the development of a 3-compartment linear PK model to describe its pharmacokinetics provides some insight.[32] A multi-compartment model suggests that after entering the central compartment (the bloodstream), the drug distributes into one or more peripheral tissue compartments before being eliminated. This is a common characteristic for many small molecule drugs. The specific tissues of distribution and the primary routes and mechanisms of metabolism (e.g., which cytochrome P450 enzymes are involved) and excretion (renal vs. hepatic) have not been detailed in the available materials.

Dose Proportionality

In Phase 1 studies, the pharmacokinetics of AL-034 were generally found to be dose-proportional within the tested range.[6] However, one single-ascending dose study (evaluating doses from 0.2 mg to 1.8 mg) noted that while systemic exposure (as measured by Cmax and AUC) increased with dose, it did so with a "slight saturation proportion to dose".[15] This language suggests a potential trend toward non-linearity at the higher end of the dose range, where a doubling of the dose might result in a less-than-doubling of drug exposure. This could be indicative of saturation of an absorption transporter or another process, though further investigation would be needed to confirm this.

Population Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling

A sophisticated population PK/PD modeling approach has been employed to integrate the drug's concentration-time profile with its biological effects (pharmacodynamics) on immune system markers.[6] This analysis yielded critical information about factors that influence patient response.

• Model Structure: The analysis utilized indirect response models, which are well-suited for describing drugs that act by stimulating or inhibiting the production or loss of an endogenous substance. These models successfully characterized the time course of key biomarkers, including the stimulation of IFN-α, IP-10 (CXCL10), ISG15, and neopterin, as well as the transient inhibitory effect on lymphocyte counts.[32] The models also incorporated complex homeostatic mechanisms, such as circadian rhythms and negative feedback loops, demonstrating a deep level of characterization of the drug's dynamic interaction with the immune system.[6]
• Key Covariate Effects: The most significant finding from the population PK/PD analysis was the identification of sex and race as important covariates influencing drug responsiveness. The analysis revealed that female participants and participants of Asian race exhibited a lower EC50 value.[32] The EC50 is the drug concentration required to produce 50% of the maximum biological effect. A lower EC50 signifies higher potency or responsiveness.

The pronounced food effect and the identified population-based variability are the most critical PK findings, carrying significant clinical and strategic implications. The greater than 50% reduction in bioavailability with food means that patient adherence to fasting instructions will be paramount for achieving predictable therapeutic exposures. Inconsistent administration could lead to highly variable drug levels, potentially resulting in sub-therapeutic effects in some instances and unexpected toxicity in others, given the dose-dependent nature of both the desired pharmacodynamic response and the adverse event profile.

Furthermore, the heightened responsiveness observed in females and individuals of Asian descent presents both an opportunity and a challenge. This finding is particularly relevant for the CHB indication, as the disease is highly prevalent in Asian populations. It could suggest the potential for enhanced efficacy in this key demographic. However, it also raises the possibility of a concomitantly higher risk of dose-dependent, on-target adverse events, such as severe flu-like symptoms. This may necessitate the exploration of different dosing strategies or dose adjustments based on these demographic factors to optimize the benefit-risk balance across a diverse patient population. These complexities will need to be carefully managed in ongoing and future clinical trial designs and would need to be clearly communicated in any future prescribing information.

Safety and Tolerability Profile

The safety and tolerability of an investigational drug are paramount considerations that determine its viability for further development. For AL-034, a consistent and predictable safety profile has emerged from Phase 1 clinical trials in healthy volunteers, which is intrinsically linked to its mechanism of action as a TLR7 agonist.

Overall Tolerability in Healthy Volunteers

Across multiple Phase 1 studies involving both single and multiple ascending doses, AL-034 has been generally reported as safe and well-tolerated when administered orally at doses up to 1.8 mg.[6] Critically, in these studies involving healthy participants, there were

no serious adverse events (SAEs), discontinuations due to AEs (with one exception for an unrelated event), or dose-limiting toxicities reported.[15]

Profile of Adverse Events (AEs)

The adverse events associated with AL-034 are characteristic of on-target pharmacologic activity, reflecting the systemic immune activation induced by TLR7 agonism and subsequent interferon production.

• Nature and Severity: The vast majority of reported adverse events were mild (Grade 1) or moderate (Grade 2) in severity. They were typically transient in nature, with symptoms like fever and flu-like illness resolving within 24 to 72 hours post-dose.[27]
• Common Adverse Events: The most frequently reported drug-related adverse events are consistent with the known effects of IFN-α exposure and are often described as a "flu-like syndrome." These include:
• Headache
• Pyrexia (fever)
• Rigors (shaking chills)
• Myalgia (muscle aches)
• Dizziness
• Nausea
• Oropharyngeal pain [15]
• Laboratory Findings: The most common laboratory abnormalities are also mechanism-based.
• Lymphopenia and Neutropenia: Transient decreases in lymphocyte and neutrophil counts are among the most common AEs. This is a known physiological effect of Type I interferon, which causes a temporary redistribution of lymphocytes from the peripheral blood to lymphoid tissues. Grade 3 (severe) but transient lymphopenia was noted, particularly in female subjects, consistent with the PK/PD finding of higher responsiveness in this group.[28]
• Other Abnormalities: At higher doses, rare instances of Grade 3 or 4 laboratory abnormalities were observed, including elevated AST (a liver enzyme), creatine kinase (a muscle enzyme), LDL cholesterol, and triglycerides.[27]

A detailed summary of treatment-emergent adverse events from the single ascending dose portion of the NCT03285620 study is provided in Table 2, illustrating the dose-dependent nature of these findings.

Table 2: Summary of Common Treatment-Emergent Adverse Events (TEAEs) in the Phase 1 Single Ascending Dose Study (NCT03285620)

Adverse Event (Preferred Term)	Placebo (N=8) n (%)	0.2 mg fasted (N=6) n (%)	0.6 mg fasted (N=6) n (%)	1.25 mg fasted (N=8) n (%)	1.25 mg fed (N=7) n (%)	1.8 mg fasted (N=6) n (%)
Headache	1 (13%)	1 (17%)	1 (17%)	4 (50%)	1 (14%)	3 (50%)
Oropharyngeal pain	0 (0%)	0 (0%)	1 (17%)	2 (25%)	0 (0%)	0 (0%)
Contact dermatitis	0 (0%)	0 (0%)	0 (0%)	2 (25%)	0 (0%)	0 (0%)
Upper respiratory tract infection	1 (13%)	0 (0%)	0 (0%)	1 (13%)	1 (14%)	0 (0%)
Pyrexia (Fever)	0 (0%)	0 (0%)	0 (0%)	3 (38%)	0 (0%)	2 (33%)
Myalgia	0 (0%)	0 (0%)	0 (0%)	1 (13%)	0 (0%)	1 (17%)
Back pain	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	2 (33%)
Dizziness	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	2 (33%)
Chills	0 (0%)	0 (0%)	0 (0%)	1 (13%)	0 (0%)	1 (17%)
Hypertension	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	2 (33%)

Grade ≥3 Laboratory Abnormalities:

• AST Increased: 1 volunteer (Grade 3) in the 1.8 mg fasted cohort.
• Creatine Kinase Increased: 1 volunteer (Grade 4) in the 1.8 mg fasted cohort.
• LDL Cholesterol Increased: 1 volunteer (Grade 3) in the 0.6 mg fasted cohort.
• Triglycerides Increased: 1 volunteer (Grade 3) in the 1.25 mg fed cohort.
• Lymphocytes Decreased: 2 volunteers (Grade 4) in the 1.25 mg fed cohort.

(Data compiled from source: [27])

The safety profile of AL-034 is highly predictable and directly understandable from its mechanism of action. The observed adverse events are not idiosyncratic or off-target toxicities but are rather the clinical manifestation of the intended systemic immune activation. The flu-like symptoms are caused by the same cytokines, particularly IFN-α, that are responsible for the symptoms of a natural viral infection. Similarly, the transient lymphopenia is a direct physiological consequence of interferon signaling. This means that the drug's "toxicity" is intrinsically and inseparable from its "efficacy." This reinforces the critical importance of identifying a therapeutic window—a dose and schedule that can elicit a sufficient therapeutic immune response to control the disease while keeping the associated systemic symptoms at a level that is tolerable for patients over a prolonged treatment course. The clinical management of these on-target AEs, potentially with supportive care such as antipyretics, will likely be a core component of the therapeutic strategy, much as it was for older interferon-based therapies.

Synthesis, Analysis, and Future Outlook

Synthesized Profile of AL-034

AL-034 (JNJ-64794964 / TQ-A3334) has emerged from a robust, multi-national development program as a potent, selective, and orally bioavailable small molecule agonist of Toll-like Receptor 7. Its profile is defined by a clear and well-characterized mechanism of action that bridges innate and adaptive immunity. By activating the TLR7 pathway, it induces a Type I interferon response that orchestrates a broad-spectrum immune activation, culminating in the generation of antigen-specific T-cell immunity. Preclinical data in a highly relevant murine model of chronic hepatitis B were exceptionally promising, demonstrating not only rapid and complete viral clearance but also a durable, sustained response post-treatment. Critically, this antiviral effect was achieved through a non-cytolytic mechanism, a feature that could provide a significant safety advantage over other immune-based therapies that risk hepatotoxicity. This preclinical promise is directly linked to the pharmacodynamic effects observed in humans, where the drug induces a dose-dependent signature of interferon-stimulated genes and immune-activating cytokines. The safety profile is a direct and predictable consequence of this mechanism, consisting primarily of transient, on-target flu-like symptoms.

Therapeutic Potential in Chronic Hepatitis B

The primary therapeutic ambition for AL-034 is to contribute to a functional cure for Chronic Hepatitis B, an objective that remains elusive with current standard-of-care nucleos(t)ide analogue (NA) therapies.[39] The strategic decision to advance AL-034 in a Phase 2 trial in combination with NAs is scientifically sound and aligns with the prevailing consensus in the field. This approach leverages a dual-pronged attack: the NA provides profound and continuous suppression of viral replication, thereby lowering the overall viral and antigenic burden on the host. This creates a more favorable immunological environment for an agent like AL-034 to successfully "re-train" or "re-awaken" the exhausted host immune system, enabling it to recognize and eliminate remaining infected cells and establish durable, long-term immune control. The potential for non-cytolytic clearance remains a key theoretical differentiator, which, if validated in patients, could make AL-034 a significantly safer and more attractive immunomodulatory component for combination regimens.

Critical Challenges and Unanswered Questions

Despite its promising profile, AL-034 faces significant hurdles that are common to its drug class, as well as specific challenges revealed during its development. Its ultimate success will depend on navigating these issues.

1. Translation of Efficacy: The most significant challenge for the entire TLR7 agonist class has been the failure to translate the profound antiviral efficacy observed in preclinical models (like woodchucks and AAV/HBV mice) into clinically meaningful and sustained HBsAg reduction in human patients at doses that are well-tolerated.[22] Several other TLR7 agonists have shown disappointing results in this regard. The pivotal question for AL-034 is whether its specific properties will allow it to break this trend and deliver on its preclinical promise.
2. The Therapeutic Index: As established, the efficacy and toxicity of AL-034 are two sides of the same mechanistic coin. The central clinical challenge is to identify a dose and schedule that can maintain a sufficient level of immune stimulation to achieve viral control over a long treatment duration (e.g., 48 weeks or more) without inducing chronic, debilitating flu-like symptoms that would severely impair patients' quality of life and lead to poor treatment adherence. Finding this delicate balance is the key to its long-term viability.
3. Management of Pharmacokinetic Variability: The clinical pharmacology data has highlighted two major sources of PK variability: a significant negative food effect and heightened responsiveness in females and individuals of Asian descent. For a drug with a narrow therapeutic index, this variability is a major concern. The development program must establish clear and effective strategies to manage this, which could include strict fasting requirements, patient education, and potentially dose adjustments based on demographic factors, to ensure consistent, safe, and effective drug exposure across a diverse global patient population.
4. Oncology Potential: The termination of the NSCLC trial (NCT04273815) leaves a major unanswered question. Was this a purely strategic decision to focus resources on the more promising CHB indication, or did it reveal a fundamental limitation of this molecule's efficacy or safety in the context of cancer therapy? Without transparency on the reason for termination, the future potential of AL-034 in oncology remains highly uncertain.

Competitive Landscape and Future Outlook

The landscape of novel HBV therapeutics is dynamic and increasingly crowded. AL-034 is competing not only with other immunomodulators but with entirely different mechanistic classes. Key competitors include:

• RNA interference (siRNA) agents: These drugs, such as bepirovirsen, directly target and degrade viral mRNA, leading to profound reductions in HBsAg levels.[40]
• Capsid Assembly Modulators (CAMs): These molecules disrupt the formation of the viral nucleocapsid, a critical step in replication.[51]
• Other Immunomodulators: This includes agonists for other TLRs (e.g., the TLR8 agonist selgantolimod), immune checkpoint inhibitors, and therapeutic vaccines, all aiming to restore host immunity through different mechanisms.[49]

The future of CHB treatment is unequivocally in combination therapy. The path for AL-034 is therefore high-risk, but also high-reward. If it can demonstrate a favorable safety profile (particularly avoiding severe liver flares) and contribute to a significantly higher rate of functional cure when added to an NA backbone—and potentially in combination with other novel agents like siRNAs—it could become a cornerstone of a curative regimen for CHB. However, it must first prove its superiority over the historical failures of its class and demonstrate a clear, compelling benefit-risk profile that can compete with other emerging modalities. The ongoing Phase 2 trial, NCT06706310, is the critical inflection point for the program. Its results will provide the first substantial evidence from a patient population and will be instrumental in determining whether AL-034 can finally translate the long-held promise of TLR7 agonism into a clinical reality for patients with chronic hepatitis B.

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