Leveraging this experience and aggregating multiple HBV-specific technologies within one company allows us to potentially accelerate delivery of an HBV cure, with potentially fewer intermediate steps in the development process. In order to accomplish this, we will target each of the three key factors, or pillars, driving chronic HBV persistence:
We believe that it is necessary to address each of these problem areas in order to deliver a successful curative combination therapy for HBV. Any such cure needs to rapidly, completely and sustainably reduce HBV viral load to undetectable levels, stimulate and reactivate the patient’s immune response in order to enable the body to fight HBV, and inhibit the formation of and eliminate viral cccDNA in the infected liver cells.
Aggressive Suppression of HBV Replication
Determining the level of viral replication at the site of infection in the liver is difficult and invasive. Because of this, alternative measurements, which utilize blood as a surrogate, are typically used. This is not ideal, because significantly more virus can be found in the liver than in the bloodstream. Although current HBV therapies do lead to undetectable virus levels in the blood in some infected patients, it is believed that low-level viral replication continues to occur in infected liver cells. The likelihood of continuing viral replication is also higher because current therapies have a limited impact on intracellular cccDNA and core DNA levels, as measured after a biopsy, suggesting that virus continues to be produced even though it is undetectable in blood serum.
Our goal is to rapidly and completely terminate the replication of HBV DNA. This involves targeting multiple steps in the viral replication process simultaneously. As in other disease states, we expect that a combination approach can lead to rapid and more dramatic drops in viral load and more thoroughly eliminate viral replication.
Restore the Host Immune Response by suppressing HBV Surface Antigen or Stimulation/Reactivation of the Immune System
Stimulation and reactivation of the host immune response is another important step in eliminating hepatitis B virus from infected patients. The European Academy for the Study of Liver Disease (EASL) guidelines state that the vast majority of people who are exposed to HBV as adults are able to rely on an effective immune response from the body in order to resolve the virus without therapeutic intervention. This suggests that a competent immune system can more often than not effectively control HBV infection. Unfortunately, a large percentage of HBV infection is passed through birth from an infected mother, and children infected with hepatitis B are the most likely to develop chronic infection, as their immune systems have not matured sufficiently to prevent chronic infection.
The hepatitis B virus uses multiple mechanisms to evade and suppress the immune system and establish a persistent infection. One of these mechanisms for immunosuppression is the release of viral proteins, particularly HBV surface antigen (HBsAg) and HBV e-antigen (HBeAg), which are secreted from infected cells in substantial excess to infectious viral particles. We have multiple programs in development targeting the stimulation and reactivation of the host immune system, including the elimination of viral proteins that inhibit the immune response.
Formation Inhibition and Elimination of cccDNA
We believe that the most important component of a combination cure for hepatitis B infection is the inhibition of viral cccDNA formation and elimination of the stable reservoir of viral cccDNA, which is deposited in the nucleus of infected cells and is the template for viral antigens and infectious virus. Although clearance of cccDNA is known to be critical to the elimination of HBV infection, the understanding of cccDNA molecular biology to date and the ability to effectively screen compounds for cccDNA inhibition has been limited. We currently have two programs directly targeting cccDNA.
We believe that we are well positioned to become a leader in the field of cccDNA-targeted therapeutics because of our existing compounds and programs and our strategic collaboration with Blumberg. Blumberg has extensive knowledge in cccDNA biology and has developed novel cccDNA screening assays that can be utilized to screen and optimize cccDNA and other viral target inhibitors. These assays have been useful in identifying novel compound series which have been valuable both as tools for studying HBV and as starting points for the development of drug discovery programs.