A development strategy to obtain IND approval of HBVZ10, a new HBV cure therapy candidate

HBV cccDNA persistence is the root cause of chronic HBV infection and cccDNA is conventionally viewed as stable in infected cells. Thus, cccDNA persistence is currently attributed to the longevity of cccDNA molecules. Current strategies to eliminate cccDNA and cure chronic hepatitis B is to directly target cccDNA or kill infected cells. Guided by clinical evidence, HBVtech uncovered that HBV infected cells may not retain cccDNA for long. HBVtech observed spontaneous cccDNA loss from infected cells during HBV infection in chimeric mice with humanized livers. Furthermore, HBVtech found that cccDNA persistence is mainly maintained by cccDNA replenishment. This discovery prompted HBVtech to test an unconventional cccDNA elimination strategy that aims to transform spontaneous cccDNA loss into a progressive cccDNA elimination through blocking cccDNA replenishment that is mainly mediated by de novo infection. A sustained high level of anti-hepatitis B surface antigen antibody (anti-HBs) is required to block de novo infection effectively and durably. However, endogenous anti-HBs antibody is usually not detectable in patients with chronic HBV infection because they are depleted by a huge pool of HBsAg particles, indicating that endogenous anti- HBs antibody production capacity that relies on specific anti-HBs-producing B cells is severely insufficient. To remedy it, HBVtech decided to expand the endogenous anti-HBs antibody production capacity through gene therapy and developed a new HBV therapy candidate HBVZ10 that utilizes an optimized AAV8 vector to deliver human anti-HBs antibody genes (AAV8-anti-HBs vector) into muscle cells. Thus, HBVZ10 transforms muscle cells into an anti- HBs antibody production factory. HBVtech has established proof of two concepts: 1. HBVZ10 potency in vivo. HBVZ10 can express sustained high levels of anti-HBs antibody after a single injection and the expressed anti-HBs antibody can effectively block de novo infection in chimeric mice with humanized livers. 2. The new cccDNA elimination strategy. Blocking cccDNA replenishment can lead to >100-fold cccDNA reduction and progressive reduction of serum HBsAg and HBeAg as well as intrahepatic HBsAg and HBc protein to undetectable level in treated mice. The FDA has granted a Pre-IND meeting on HBVZ10 IND studies, and issued the detailed written responses, which serve as a clean map for HBVZ10 IND studies. The specific goal of this planning project is to assemble a team including HBVtech, clinical investigators, CROs, regulatory, CMC, and business consultants and propose specific pharmacology, CMC, toxicology, and clinical plans required to obtain IND approval of HBVZ10 from FDA.