Therapeutic Safety and Efficacy of REP 9AC (REP 2055) in HBV or HCV Infected Patients
Condition: Hepatitis B, Chronic
MeSH terms: Hepatitis B; Hepatitis B, Chronic
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      REP 9AC (REP 2055) is a nucleic acid polymer (NAP) with entry activity against hepatitis C
      virus and entry and post-entry antiviral activity against duck hepatitis B virus (DHBV)
      infection. REP 2055 has been shown to have potent prophylactic effect against HCV infection
      in vivo and potent therapeutic effect against established DHBV infection in vivo

      The REP 101 protocol is the first-in-man proof of concept study designed to investigate the
      safety and antiviral activity of REP 2055 administration in human patients with chronic HBV
      or HCV infection.
    

Detailed description: 
      Chronic hepatitis B and C are long term conditions caused by infection of the body with the
      hepatitis B (HBV) and C (HCV) viruses. These infections often result in inflammation or
      scarring of the liver and can eventually lead to liver cirrhosis and liver failure. These
      infections are also one of the major causes of the development of hepatocellular carcinoma
      (liver cancer).

      Although some drugs have been approved to treat chronic hepatitis B infections, they do not
      provide a complete cure except in rare cases (a cure generally means that a person loses the
      hepatitis B virus and develops protective surface antibodies). However, these drugs
      significantly decrease the risk of liver damage from the infection by slowing or stopping the
      virus from reproducing. Amongst the problems associated with currently available drugs are
      the tendency to develop resistance and the lack of clearance of the virus from the
      hepatocytes. There is clearly a need to identify new drugs that can benefit patients with
      chronic hepatitis B infections. REP 9AC is a 40mer phosphorothioate oligonucleotide that has
      been shown to have low toxicity and to be highly effective to treat hepatitis B infection in
      animals. It has been shown to be effective in protecting animal from infection and to treat
      animals already infected.

      The efficacy of REP 9AC (REP 2055) in duck hepatitis B has been tested in collaboration with
      Dr. Allison Jilbert (University of Adelaide, Australia), who is a recognized expert on HBV
      infections. These results suggest that REP 2055 can completely eliminate the disease in a
      large proportion (50%) of animals following only 4 weeks of treatment. In other words,
      following cessation of the treatment, the viral titer does not return. If these results are
      replicated in humans, this will result in a paradigm shift in how patients with hepatitis B
      are treated. Currently available drugs can only control the disease. Once they are stopped,
      the viral titer returns.

      This proposed study is designed to demonstrate that REP9AC can be well tolerated when given
      to human patients chronically infected with HBV and to evaluate if a reduction of viral
      titers can be observed when REP 9AC is administered as a monotherapy. Current interim data
      analysis from the REP 101 trial indicates the following:

        1. REP 9AC is generally well tolerated at doses up to 600mg / week in all patients
           currently enrolled and in HBV patients at 400mg / day (for seven continuous days).

        2. REP 9AC has resulted in both HBV patients achieving protective seroconversion (anti-HBs)
           and clearance of HBV DNA and HBsAg in their blood by 23 weeks after initiation of
           treatment.

        3. Increasing frequency and dose of REP 9AC treatment at the start of therapy may provide
           more rapid seroconversion of HBV patients.

        4. Increasing frequency and dose of REP 9AC treatment at the start of therapy may provide
           better efficacy for HCV patients.

      Hepatitis C. Recent advances in the treatment of hepatitis C, using interferon and ribavirin
      combination therapy, have brought overall response rates to about 50% but these responses are
      associated with significant costs and toxicities. In view of the lack of response of many
      patients to standard therapy and in view of its associated toxicities, the development of new
      therapeutic strategies is critically important. Amphipathic polymers have been shown to have
      broad spectrum antiviral activities and to have very favorable pharmacokinetics in the liver
      making them ideal candidates for the therapy of viral hepatitis B and C.

      In collaboration with Dr. Jake Liang, (Head, Liver Diseases Branch, National Institute of
      Health, USA), REP 9AC has been shown to provide complete protection from HCV infection in
      naïve animals. REP 9AC is perfectly suited for the treatment of chronic HCV infection as
      exposure to this drug will allow the liver to naturally eliminate infected cells by halting
      the continual cycle of infection of healthy liver cells. REP 9AC may eventually replace
      pegylated interferon and ribavirin as the standard of care owing to its activity against all
      genotypes of HCV and its novel mechanism of action, which does not promote the generation of
      drug resistance.

      An entry inhibitor could be useful when used in combination therapy or could be effective as
      a monotherapy. This proposed study is designed to demonstrate that REP 9AC can be well
      tolerated when given to patients chronically infected with HCV and to evaluate if a reduction
      of viral titers can be observed when REP 9AC is administered as a monotherapy.

      REPLICor's technology utilizes the novel properties of modified oligonucleotides
      (phosphorothioate oligonucleotides) as amphipathic polymers to inhibit interactions critical
      for viral activity. This technology is active in vitro against all known families of
      enveloped viruses. REPLICor's proof of concept compounds, REP 9 (REP 2006) and REP 9C (REP
      2031) and its lead compound, REP 9AC (REP 2055) have also demonstrated potent antiviral
      activity in vivo against the following viral infections: HCV, HBV (DHBV), Cytomegalovirus,
      Herpes simplex virus-2, Ebola, influenza and respiratory syncytial virus.

      REP 9, REP 9C and REP 9AC have been administered at therapeutically active doses in acute and
      chronic regimens by multiple routes of administration (parenteral, oral, topical and aerosol)
      in mice, rats, hamsters, guinea pigs, ducks and non human primate species with no detectable
      side effects. Moreover, this class of chemical compounds (phosphorothioate oligonucleotides)
      are known to have been well tolerated in human patients in several clinical trials.
    

Intervention name(s): REP 2055
Intervention type(s): Drug
Intervention description(s): (First two patients) REP 2055 is administered once weekly by slow IV infusion in dose escalation from 100 to 1200mg until a grade 3 adverse event is observed not to exceed 40 weeks of dosing.
(Subsequent patients) 400mg of REP 2055 is administered by slow IV infusion. First week of infusion to include daily dosing followed by twice weekly dosing for 40 weeks.
Other intervention name(s): REP 9AC
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment