Hepatitis B

There are an estimated 292 million patients with chronic hepatitis B (HBV) infection worldwide. More than 880,000 people die from complications directly related to their chronic HBV infection every year. Current therapies can provide control of the virus but suffer from an inability to remove antigen burden (HBsAg) from patients, an essential step required to restore functional control of infection, which remains after current treatments are withdrawn.

What is Hepatitis B?

The hepatitis B virus (HBV) infects the liver and causes inflammation (hepatitis). More than 2 billion people worldwide have been infected with HBV, leaving an estimated 292 million people with chronic HBV infection. In the vast majority of people who have resolved their infection, it is actually still present in the liver but in a latent state because of effective and continual control by their immune system. In patients who cannot establish this immune control, HBV infection becomes chronically active. In these patients, chronic HBV infection causes liver inflammation, which can lead to fibrosis and cirrhosis. In addition, integration of viral DNA in the host chromosomes disrupts their normal function, and the progressive accumulation of these integration events may lead to liver cancer. As a result, a significant proportion of patients with chronic HBV infection will eventually die from these complications without treatment. For more information on HBV, please visit the World Health Organization website here.

The problem with current treatments for HBV infection

Currently approved therapies for HBV either attempt to improve the immune function of the patient to control the virus (interferons) or prevent the release of infectious virus by blocking the enzyme that is responsible for the maturation of the virus into its infectious state (HBV reverse transcriptase inhibitors like entecavir [ETV] and tenofovir disoproxil fumarate [TDF]). Both of these approaches suffer from important drawbacks: interferons can only restore control of infection that persists after therapy (“functional cure”) in a small number of patients (typically < 10%), which makes the side effects accompanying this therapy difficult to justify. On the other hand, drugs like ETV and TDF work well to control the virus in most patients but rarely achieve functional cure when these medicines are stopped, making them a life-long treatment.

New approaches to treating HBV

Recent years have seen the emergence of many new approaches to controlling the virus, most notably those agents which block the assembly of the viral capsid (the protein shell underneath the viral membrane which houses the viral DNA) or block the activity of HBV “minichromosomes” (cccDNA) which stably reside in the nucleus of the cell and are the source for the production of the new virus.

The HBsAg problem – the critical path to restoring functional cure of HBV infection

In chronic HBV infection, the blood is saturated with the surface antigen protein (HBsAg) by the production and release of small viral-like particles called subviral particles (SVP). These particles are not infectious but make up the bulk of viral protein in the blood (> 99.99%) and are packed with the HBsAg protein. SVPs are a naturally evolved mechanism of HBV infection that function to neutralize antibodies to the virus and, more importantly, to suppress other aspects of host immune function required to effectively control HBV infection. Thus the abundant levels of circulating SVPs not only allow HBV infection to persist chronically by blocking immune function but also prevent the restoration of immune control of HBV infection by immunotherapies like interferons, TLR agonists, and therapeutic vaccines.

Targeting the HBsAg protein is especially difficult because: 1) HBV can rapidly evolve to escape the actions of drugs, and 2) the assembly of SVP is a lipid-mediated process. Both these features of HBV infection make inhibiting HBsAg release difficult to achieve with small molecule or antisense / siRNA based-approaches. Additionally, HBV DNA in its integrated state in host chromosomes can produce HBsAg as SVP in the absence of viral replication and, as such, is not affected by antiviral technologies that target the classic steps of viral replication (i.e., capsid assembly inhibitors and cccDNA inhibitors as described above.)

Nucleic acid polymers can allow restoration of functional control of HBV infection

Replicor’s lead nucleic acid polymer (NAP) compound, REP 2139, is built from synthetic RNA designed to be non-reactive to the host immune system like naturally occurring RNA inside the human body. As such, REP 2139 naturally and safely accumulates inside hepatocytes where it prevents the assembly and secretion of SVPs from being produced from cccDNA or integrated HBV DNA. This ubiquitous effect of REP 2139 drives its unique ability to effectively block replenishment of HBsAg in the blood, allowing host-mediated clearance of HBsAg to proceed.

The clinical impact of REP 2139 when added to the existing standard of care

In pre-clinical and clinical studies in HBV infection, REP 2139 therapy by itself is accompanied by rapid declines in HBsAg in the blood. As a result of the removal of this immunosuppressive antigen burden, many other antiviral responses accompany the primary effect of REP 2139 therapy and include:

  1. HBsAg seroconversion.
  2. HBeAg seroconversion (in HBeAg positive patients).
  3. Clearance of HBV DNA and HBV RNA (defective, non-infectious virus).
  4. Early inhibition of viral replication (cccDNA).
  5. Early reduction of intracellular HBsAg, HBV DNA, and cccDNA in pre-clinical studies.
  6. Persistent control of HBV infection in the liver after removal of all therapy in pre-clinical studies (inactive cccDNA, low or undetectable HBsAg) “functional cure.”

With the removal of HBsAg to levels below 1 IU/mL occurring in most patients (typically 3-5 log reduction from baseline), the addition of different immunotherapies is accompanied by evidence of restoration of immune control:

  1. Dramatic and rapid elevations of antibodies to the HBsAg protein.
  2. The appearance of safe and asymptomatic (therapeutic) transaminase flares in most patients consistent with the clearance of infected hepatocytes from the liver.
  3. The establishment of persistent control of HBV infection and normal liver function after removal of all therapy in 85% of patients completing therapy, consistent with the restoration of immune control.

These on-treatment and off-treatment results are unmatched by any other single drug or combination of drugs either approved or in development.