Hepatitis B
There are 400 million hepatitis B (HBV) patients worldwide. It is estimated that about 100 million of these patients will eventually die from complications directly related to their chronic HBV infection despite available therapies. Current therapies have been associated with several problems including viral resistance, significant toxicities and the lack of a curative response even after many years of therapy.
Our drug is a first-in-class surface antigen release inhibitor. It prevents the release of a viral protein called surface antigen from infected liver cells (hepatocytes). Mounting evidence is now showing that surface antigen acts to suppress the immune response to HBV infection and may allow the infection to be chronically maintained in the liver. The administration of our drug to animals or humans results in a rapid reduction and elimination of surface antigen in the blood. This reduction is associated with a restoration of the immune system’s capability to fight the infection as demonstrated by the development of antibodies against surface antigen. In other words, the removal of surface antigen from the blood gives patients the ability to successfully fight their infection on their own. In addition, because of its mechanism of action, the development of resistance to our drug is very unlikely.
In collaboration with scientists from the University of Adelaide, Australia, REPLICor has tested the antiviral potential of its drug in ducks infected with duck hepatitis B viruses, a recognized animal model that is a good predictor of antiviral activity in human subjects. We have shown that a 4 week daily treatment regimen with our drug was able to result in a curative response in more than half of DHBV-infected ducks treated. This is the first time any such curative response has been achieved in this model and has not been achievable with drugs currently marketed for the treatment of HBV.
Interim clinical data from our phase I/II trial shows that our drug is well tolerated and has substantial antiviral activity in patients suffering from chronic HBV infection. The administration of our drug results in the rapid elimination of surface antigen and the appearance of antibodies in most patients. This is followed by a substantial reduction of viral DNA titers.
NUCLEIC ACID-BASED POLYMERS (NAPS)
A novel therapeutic activity for the treatment of chronic hepatitis B.
NAPs were discovered at REPLICor in 2002 and utilize the unique, sequence independent properties of phosphorothioated oligonucleotides to generate a novel amphipathic polymer which has a very broad spectrum antiviral activity against enveloped viruses. After several years of research, REPLICor has now shown that these compounds effectively block the release of the hepatitis B surface antigen (HBsAg) from liver cells infected by the hepatitis B virus (HBV).
HBsAg was first described as the Australian antigen by Dr. Baruch Blumberg in 1967 (a discovery which won him the Nobel Prize for Medicine in 1976). This viral antigen is produced in large quantities by infected hepatocytes and many studies have now shown that the release of HBsAg into the blood blocks the function of the immune system and prevents it from mounting an effective attack on the HBV infection (see the figure below). This inhibition of the immune system by HBsAg is one of the main reasons why HBV infection persists for so long. In fact, HBV infection can be described as a chronic immunological disorder as well as a viral infection.
NAPs block the release of HBsAg by preventing the release of subviral particles from infected hepatocytes. Since subviral particles are the major “cargo carriers” for HBsAg, preventing their release is a highly effective method to stop the release of HBsAg into the blood. Thus, by blocking subviral particle release, NAPs effectively remove the majority of immunosupressive activity of HBV infection (as shown for the clinical NAP REP 9AC below).
A major advantage of NAPs is that they concentrate in the liver naturally, without the aid of any delivery system, which serves to concentrate the pharmacologic activity of NAPs where they are needed most, in the infected hepatocytes in the liver. This combination of efficient liver targeting with the potent ability to supress HBsAg release has led to very encouraging preliminary clinical results with REPLICor ‘s clinical NAP candidate, REP 9AC.
In a preliminary Phase I / II protocol, REP 9AC has effectively cleared HBsAg from the blood of seven patients with chronic HBV infection with relatively short treatment regimens and the resulting “re-activation” of immunity in these patient’s has led to profound results:
We have been able to detect antibodies to the HBsAg protein in all seven patients – a very good prognostic indicator.
All patients achieved a minimum 1000-fold reduction in levels of virus in their blood.
We have three patients with durable immunological control of their infection 12-24 months after stopping infection which has resulted in a reversal of their liver damage caused by their chronic HBV infection. This is as close to a curative response as has been achieved yet with any drug.
REPLICor is currently working to perfect this technology in a series of clinical trials designed to optimize the tolerability and ease of administration of REP 9AC.
