Treating viral hepatitis28/11/17
Researchers at Replicor Inc. are using a new approach to achieve high rates of functional remission in patients with chronic hepatitis B and hepatitis D infections
UP to 350 million people worldwide are affected by chronic hepatitis B (HBV) – a viral infection that affects the liver. Over time, this infection causes progressive liver damage, leading to cirrhosis and liver cancer. Vaccines are effective in preventing HBV infection but have no effect if the illness is previously established. Transmission occurs through bodily fluids or maternal transmission at birth from an infected mother. Current therapies consist of two main classes of drugs. The first class, called nucleos(t)ide analogs (or NUCs), reduces the amount of infectious virus in the liver and in the blood. NUCs slow the progression toward cirrhosis but need to be administered for the lifetime of the patient since the removal of NUCs leads to a reactivation of infection. The second class of drugs includes immunotherapies such as interferon and thymosin alpha 1. These drugs stimulate the body’s immune response to the infection.
The new goal of modern HBV treatments is to restore a functional remission of the infection (little to no evidence of infection with normal liver activity without any treatment). The rate of functional remission achieved, even with NUCs combined with immunotherapy is less than 10%. The main reason that functional remission is so hard to achieve is that infected liver cells also produce a large excess of defective viral particles containing a viral protein called HBsAg (HBV surface antigen). This protein blocks the immune response against HBV infection, blocks the ability of immunotherapy to restore immune function and is not affected by NUCs. The inability to restore the immune response in the presence of HBsAg makes it very difficult to establish functional remission with currently available treatments. There is therefore an important unmet medical need for developing new drugs that can eliminate the HBsAg protein, a key step in achieving higher rates of functional remission.
Replicor has developed a new class of drugs called nucleic acid polymers (NAPs) that promises a revolution in the treatment of chronic HBV infection. NAPs prevent the release of HBsAg into the blood, allowing its elimination from the blood of infected patients. Replicor’s clinical trials have shown that when HBsAg reductions to below 1IU/mL are achieved (typical for NAPs), immunotherapy can efficiently re-establish immune control of the infection in a high proportion of patients, resulting in functional remission of HBV infection.
The efficacy and safety of our drug has already been successfully demonstrated in several small phase II human clinical trials in Asia and eastern Europe. The most effective treatment to date can typically only achieve a less than 10% rate of functional remission. Based on current results, it is projected that a functional remission rate of up to 80% will be achieved when using current NAP-based combination treatment regimens with approved medications.
Patients achieving functional remission in this study have no detectable HBsAg or virus in their blood and their liver function return to normal without the need for any additional treatment. No other drug either approved or in development is able to completely eliminate HBsAg from the blood in such a large proportion of patients.
Additional studies are being planned to compare the safety and efficacy of combining NAPs and NUCs with either Pegasys or thymosin alpha-1. Our preliminary observations suggest that the combination using thymosin alpha-1 will be better tolerated and more effective than a combination using Pegasys. Another study will be to assess if patients on long-term NUC therapy with lower HBsAg levels could achieve functional remission when receiving NAPs without the need of added immunotherapy.
The hepatitis D virus (HDV) only infects patients who already have HBV or simultaneous infection. Co-infection with HBV and HDV is the most aggressive form of viral hepatitis leading to a high rate of cirrhosis. The co-infection affects 15 to 20 million persons worldwide. Interferon has shown some degree of activity against this infection, but a large proportion of patients relapse once the therapy is stopped.
No drug has been approved for treating HDV infection, making this infection an orphan indication with the possibility of accelerated approval by regulatory agencies. In a recent clinical trial, Replicor has shown that seven patients out of 11 who completed therapy had functional remission of their HDV infection after receiving NAPs in combination with interferon (Pegasys) making our NAPs the most promising asset in this field. These results were recently published in The Lancet Gastroenterology & Hepatology. This functional remission is currently lasting 18 months after the end of therapy, showing the long-lasting improvement in immune function achieved by this approach.
Longer and more optimised NAP-based combination therapy regimens now demonstrated to show high rates of functional remission of HBV are also expected to achieve the same high rates of functional remission of HDV infection.
Our pre-clinical and clinical results have been presented at many major conferences in the field. These can be accessed on our website at: http://replicor.com/science/conference-presentations/
A list of peer-reviewed publications on NAPs can be accessed at this link: http://replicor.com/science/publications/
Replicor has an extensive patent portfolio covering methods of treatment, composition of matter, pharmaceutical compositions and formulations providing protection until 2035.
Massive progress has been made in the treatment of hepatitis C where cure rates up to 99% can now be achieved. HBV and HDV infections have proven more difficult to treat, but Replicor is proud to be on the front line of the development of a new therapy for these important liver infections.