Long-acting Antiviral Treatment for HBV

ABSTRACT The overarching goal of this collaborative and translational research on hepatitis B (HBV) is to discover a safe and effective long-acting antiviral (ARV) therapy that can provide sustained viral suppression. The current daily and chronic oral antiviral dosing for HBV patients causes pill fatigue and leads to fluctuating drug levels. Both

aspects lead to viral rebound and increases the risk of liver cancer. The introduction of Cabenuva, a long-acting HIV drug product containing two injectables (cabotegravir and rilpivirine two different products used in combination), has been a game-changer for the AIDS community, addressing pill fatigue and other barriers.

However, patients co-infected with HBV and HIV are not benefiting fully from this long-acting HIV therapy. To mitigate the risk of HBV rebound and progression to cirrhosis and/or liver cancer, there is an urgent need for a long-acting HBV product that can provide sustained viral suppression, alleviate pill fatigue, and ensure consistent

antiviral coverage for both people with HBV and HBV-HIV. The proposed translational research aims to leverage the expertise and collaborative capacity of the investigative team to transform current best, oral antiviral drugs that is short acting into a long-acting HBV therapy. With extensive resources and a proven track record in preclinical and clinical antiviral research and product translation,

our goal is to identify a lead and backup product candidate suitable as monthly self-injectable long-acting HBV therapy. The intent of the HBV therapeutic candidate it is for use alone or in combination with existing long-acting HIV therapies like Cabenuva. The proposed approach utilizes a well-established platform technology to develop

innovative and new long-acting anti-HBV products, with the potential to achieve longer-lasting viral suppression and improve HBV therapeutic outcomes. Our research plan incorporates a set of success matrices and aims based on a defined target product profile (TPP), with guidance from an external scientific advisory board (SAB). The research aims are: (1) identifying lead

and backup antiviral compositions and processes through molecular-level drug-lipid (excipient) interaction studies to define the characteristics of long-acting products, (2) evaluating and defining pharmacokinetic profiles of long- acting dosage forms in vivo to identify lead and backup candidates, (3) identifying preferred user characteristics for

long-acting HBV therapy among people living with HBV, and (4) verifying antiviral activity through dose-response pharmacokinetic evaluation in a primate model and a woodchuck hepatitis model. This five-year translational research progress from in vitro drug-lipid interaction studies to the evaluation and

selection of a lead and backup long-acting anti-HBV therapy for preclinical and clinical development. The study results will inform early discussions with the FDA and the FDA guidance received will serve as the foundation for seeking NIH to support the manufacturing of GMP materials and GLP toxicokinetic studies, thereby advancing our

overarching goal of developing a novel long-acting HBV therapy for individuals living with HBV.