A Single Long-Acting Injection For HBV Treatment Using Novel Entecavir Prodrugs For PWLH

About This Grant

ABSTRACT The long-term objective of this research is to develop a long-acting injectable (LAI) therapy for hepatitis B virus (HBV) in individuals co-infected with human immunodeficiency virus (HIV). This project is of significant health relevance as approximately 10% of the 1.2 million people living with HIV in the United States are co-infected with HBV. Effective management of both infections is crucial to prevent accelerated liver damage, improve health outcomes, and enhance the quality of life for this population. As LAI therapies have improved HIV management, to improve management of HIV/HBV co-infections there is a need to develop a complementary LAI for HBV. The proposed research aligns with the mission of NIH and NIAID to advance innovative therapeutic approaches and improve public health. In the R61 phase, the specific aims are to optimize the current lead entecavir prodrug (mCMQ657) to achieve sustained release and maintain therapeutic levels for up to three months. This will involve pre-formulation and formulation development to ensure the stability and bioavailability of the long-acting entecavir prodrug. Preclinical pharmacokinetic (PK) and pharmacodynamic (PD) studies will be conducted to determine safety, efficacy, and optimal dosing regimens in animal models. Additionally, toxicology and safety pharmacology assessments will be performed to support the identification of a development candidate and transition to the R33 phase. The R33 phase will focus on Investigational New Drug (IND)-directed development activities, including the development of good manufacturing practice (GMP) processes, good laboratory practice (GLP) toxicity studies, and preparation for future clinical trials. This phase will involve engaging with regulatory authorities to schedule and complete a pre-IND meeting with the FDA. The research design and methods for achieving these goals are comprehensive and rigorous. The project will leverage the expertise of the research team and include collaboration with translational advisors and regulatory advisors. Pre-formulation studies will involve characterizing the physicochemical properties of mCMQ657, while formulation development will focus on creating a stable and effective LAI formulation. PK and PD studies in relevant animal models will assess the prodrug’s pharmacological profile and therapeutic potential. In summary, the successful development of an LAI for HBV in HIV/HBV co-infected individuals aims to reduce the burden of daily medication adherence from a daily oral pill to a once-monthly injection, enhance patient compliance, and ultimately improve clinical outcomes by providing a more effective and convenient treatment option. This approach is expected to significantly impact the treatment landscape for HBV and HIV co-infections and contribute to the advancement of long-acting therapies in infectious diseases.