A New HBV Drug For Establishing Durable Antiviral Efficacy of HBV Treatment

It is estimated that 292 million people in the world are chronically infected with hepatitis B virus (HBV). Nearly 1 million patients died from HBV related liver diseases each year. HBV treatment with interferons and nucleos/tide analogues or new drugs face two challenges: 1. Can’t achieve sustained antiviral efficacy and drug withdrawal frequently leads to HBV relapse and flares up of liver injury, outcomes of which can be severe or fatal; and 2. Rarely cure HBV infection after many years of treatment. A key step should be taken to reach the goal of HBV functional cure set by NIH and FDA, i.e. developing new HBV drugs that aim at achieving durable antiviral efficacy of HBV treatment and allow drug cessation without HBV relapse. HBV drug withdrawal lifts inhibition of HBV replication, leading to producing and releasing more virions that will infect more cells, i.e. HBV relapse, because of insufficient anti-HBs antibody that can’t match HBV particle level, leaving virions unneutralized, facilitating new spreads of infection or HBV relapse. Thus, the fundamental problem causing HBV relapse after drug stops is a lack of sufficient anti-HBs antibody, which is associated with defects in HBsAg-specific B cells. To effectively address this significant challenge of non-durable antiviral efficacy of HBV therapy, endogenous anti-HBs production must be expanded independently of B cells. HBVtech aims to develop AAV vector-based gene therapy to expand endogenous anti-HBs production capacity. To develop this new therapy, HBVtech must establish two in vivo feasibilities: 1. ability to express sustained high level of anti-HBs; and 2. the expressed anti-HBs antibodies being capable of blocking HBV infection in HBV infected chimeric mice. HBVtech has constructed four AAV anti-HBs vectors that carry anti-HBs genes for expressing anti-HBs antibody. Subsequently, HBVtech evaluated the in vivo expression ability of each AAV-anti-HBs vector in mice and has proven the first ability that three of four AAV-anti-HBs vectors can express high level (andgt;100?g/ml) of anti-HBs antibodies for at least 25-week in transduced mice. This proven ability to express sustained high level of anti-HBs antibody by AAV vectors has laid the critical foundation for the success of this drug. The objective of this Phase I study is to ascertain the 2nd ability that the expressed anti-HBs by three AAV-anti-HBs vectors effectively blocks in vivo HBV infection by establishing durable efficacy after entecavir stops. By completing this phase I study, two key in vivo feasibilities will have been established. HBVtech will file new patent application to protect AAV-anti-HBs vectors. Three AAV-anti-HBs vectors will enter phase II development. If successful, this new HBV therapy will shorten infinite HBV treatment to a finite course and benefit millions of patients, representing a critical progress in HBV cure.NARRATIVE This project aims to develop a new hepatitis B virus (HBV) drug that constantly block new expansions of HBV infection after current HBV treatment stops. Thus, this new HBV therapy is expected to establish durable efficacy of hepatitis B treatment, shorten lifetime treatment to a finite course and benefit millions of hepatitis B patients.