The Novira Therapeutics Approach
Novira Therapeutics’ goal is to develop small molecule drugs that provide the opportunity for a functional cure within one year or less of treatment for a majority of patients with CHB infection. Two key characteristics render HBV infection curable: 1) The cccDNA mini-chromosome is not maintained by cellular mechanisms and can therefore be lost after hepatocyte cell death or division and 2) The key target cells of HBV infection, hepatocytes, are short-lived and are continuously replaced by new hepatocytes. Therefore, greater functional cure rates will be possible when using therapies that prevent the infection of new hepatocytes and lead to elimination of the infected hepatocyte pool. This will be accomplished by novel drugs that can either completely suppress HBV replication and shut down virion production and new cell infection, and/or restore a functional immune response against the virus.
Our world-class team of chemists and biologists are focused on the discovery and development of two classes of novel anti-HBV drugs to deliver a functional cure: Core/capsid Inhibitors and cccDNA Inhibitors.
Novira Therapeutics is leading the discovery and development of Core/capsid Inhibitors (CI), small-molecule, direct acting antiviral agents that disable the function of the HBV Core protein through allosteric modulation (e.g., conformational change). Depending on the binding mode and corresponding conformational change, Core Inhibitors have the potential to disable one or more HBV Core protein functions. The roles ascribed to the HBV Core protein and corresponding impact of Core Inhibitors in CHB infection are illustrated in Figure 3.
Core Inhibitors are expected to reduce and eventually eliminate the pool of infected hepatocytes leading to improved functional cure rates through the following mechanisms: 1) Blocking infection of new hepatocytes, 2) Complete suppression of HBV replication (shut down production of new virions) in combination with existing HBV drugs, and 3) Restoration of the host innate immune response by induction of Interferon Stimulated Gene expression (ISG induction).
HBV Core Inhibitors such as NVR 3-778 are believed to bind to all oligomeric forms of HBV Core such as the HBV Core dimer (the capsid building block) and the assembled HBV capsid (protein shell composed of 240 copies of HBV Core). There is evidence that binding of Core Inhibitors to the HBV capsid can prevent productive infection after viral entry by blocking steps required for the formation of cccDNA and accumulation of HBV Core in the nuclei.
Figure 3 depicts the potential contributions of NVR 3-778 to the functional cure of CHB infection through inhibition of the HBV Core dimer. The biological activities of HBV Core that are required for HBV persistence include:
- Core dimer is the building block for assembly of the viral capsid. Core Inhibitors promote the formation of abnormal, dysfunctional viral capsids and thereby block production of infectious virus progeny.
- The viral capsid can exit the hepatocyte or traffic back to the nucleus to replenish and maintain a stable number of cccDNA molecules. Core Inhibitors can also block cccDNA replenishment and contribute indirectly to inhibition of HBV replication.
- Core binds the promoter regions of interferon stimulated genes (ISG) in the host chromosome to inhibit ISG expression and suppress the host innate immune response. Core Inhibitors that can induce ISG expression may restore the anti-HBV host innate immune response, leading to non-cytolytic clearance of infected hepatocytes.
- Core binds cccDNA and maintains the mini-chromosome in a transcriptionally active state, thus allowing continuous production of new virus. Core Inhibitors that can prevent binding of Core to cccDNA will silence the cccDNA mini-chromosome. Silencing of cccDNA can prevent production of virus progeny and may restore host anti-HBV immune response.
Core Inhibitors have the potential to inhibit all of these activities. Complete suppression of infectious virus production and restoration of host innate immune response could lead to enhanced elimination of infected hepatocytes and, thus, greater functional cure rates in patients with chronic infection.
Novira Therapeutics has developed an efficient and proprietary HBV infection system that recapitulates cccDNA-dependent persistent or chronic infection of hepatocytes in cell culture. We are using this system to screen compound libraries and identify small molecule drugs that can either silence or degrade cccDNA by monitoring the effect of compounds on HBsAg production from cccDNA. These efforts have led to the identification of multiple promising classes of cccDNA Inhibitors that are being optimized and prepared for preclinical development.