Novel Long-Acting HBV Capsid Assembly Modulators

OF PROPOSED RESEARCH Antiviral nucleoside analogs have proven effective in treating chronic hepatitis B (CHB) and improving the survival and quality of life for those living with CHB. However, a cure remains elusive. Currently, individuals with CHB, including those co-infected with HIV, require lifelong oral medication to suppress the virus to undetectable levels. Challenges related to medical adherence and limited access to drugs persist, underscoring the need for long-acting release formulations. Capsid assembly modulators (CAMs) represent a promising class of antivirals that disrupt the HBV capsid assembly process, preventing the encapsidation of pregenomic RNA and inhibiting viral replication. Furthermore, at higher concentrations, CAMs impede the transcription and de novo formation of covalently closed circular DNA (cccDNA) in the early stages of infection. ALG-001075 is a proprietary, novel, pan-genotypic CAM with sub-nanomolar in vitro potency. Its oral prodrug, ALG-000184, is currently being evaluated in clinical trials involving individuals with CHB, where it has shown unprecedented reductions in HBV DNA, RNA, and viral antigens, as well as superior HBV DNA reduction compared to nucleoside analogs. As the active metabolite of ALG-000184, the exceptional potency, dual anti-HBV mechanism, and safety profile position ALG-001075 as a strong candidate for long-acting regimens. This study aims to develop a biodegradable and biocompatible nanoparticle (NP) injectable sterile formulation that encapsulates ALG-001075 for prolonged release. This sustained drug release can extend the dosing interval from daily to monthly or even longer, providing significant benefits for individuals living with CHB or co-infected with HIV/HBV. Enhanced drug efficacy due to improved adherence and reduced costs will be particularly beneficial in areas lacking birth dose vaccination or in low-resource settings, where HBV carrier rates are extremely high. The specific aims are: 1) To formulate and optimize an NP delivery system for ALG-001075 that achieves extended in vitro release for at least one month (R61 phase); 2) To determine the pharmacokinetics of ALG-001075 following NP delivery (R61 phase); 3) To evaluate the in vivo antiviral efficacy of long-acting ALG-001075 in HBV mouse models (R61 & R33 phases); 4) To manufacture the drug substance and drug product to facilitate toxicology studies (R33 phase); 5) To assess the in vivo safety of long-acting ALG-001075 (R33 phase). To achieve these goals, we will initially explore the encapsulation of ALG-001075 in biodegradable polymeric NPs or lipid NPs. Formulations will be evaluated in vitro to assess release kinetics and stability and in rodents to establish exposure durability and efficacy. In the R33 phase, we will utilize existing procedures for synthesizing ALG-001075 to manufacture the drug substance and prepare a long-acting formulation that can proceed to IND-enabling toxicology studies. With the IND-directed product development strategy, we anticipate that at least one NP design will meet the requirements and advance to IND filing. Project Number: 1R61AI197036-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Raymond Schinazi (+2 co-PIs) | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $954,603 | Activity Code: R61 | Study Section: Special Emphasis Panel[ZRG1 IIDB-K (51)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R61AI19703601