REP 2139-Mg and REP 2165-Mg Combination Therapy in Chronic Hepatitis B Infection
Condition: Chronic Hepatitis B
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic
Study type: Interventional
Phase: Phase 2

Summary: 
      NAPs have been previously shown to clear serum hepatitis B virus surface antigen (HBsAg) both
      preclinically (in duck HBV infected ducks) and in human patients. REP 2139-Ca mediated HBsAg
      clearance acts synergistically with immunotherapeutic agent pegylated interferon-alpha 2a to
      restore host immunological control of HBV infection. REP 2165 is a version of REP 2139 which
      has been shown preclinically to retain antiviral activity with lower accumulation in the
      liver.

      Both REP 2139 and REP 2165 used in this protocol are formulated as magnesium chelate
      complexes, which improve their administration tolerability. This open label, randomized and
      controlled study will examine the safety and efficacy of REP 2139-Mg and REP 2165-Mg therapy
      in patients with HBeAg negative chronic hepatitis B when used in combination with tenofovir
      disoproxil fumarate and pegylated interferon alpha-2a.
    

Detailed description: 
      Nucleic acid polymers (NAPs) utilize the sequence independent properties of phosphorothioated
      oligonucleotides to target apolipoprotein interactions involved in the formation of HBV
      subviral particles (SVPs) which are comprised mainly of the hepatitis B surface antigen
      protein (HBsAg). The effect of NAPs is to block the formation of SVPs inside infected
      hepatocytes which prevents their secretion. As SVPs account for > 99.99% of HBsAg in the
      blood, NAPs are an effective approach for clearing HBsAg from the serum of HBV infected
      patient.

      Previous clinical trials have demonstrated that treatment with the NAP REP 2139 (REP 2139-Ca)
      results in the rapid and effective clearance ofHBsAg from the blood. This HBsAg removal has
      the immediate effect of unmasking the underlying, pre-existing anti-HBsAg (anti-HBs)
      response, allowing clearance of HBV virus from the blood.

      Although REP 2139-Ca has been shown to be safe in human patients, it shares the same class
      effect as other phosphorothioate oligonucleotides in that it accumulates in the liver with
      repeated dosing. REP 2165 is a version of REP 2139 which is designed to have an increased
      rate of degradation to slow down liver accumulation while keeping its antiviral activity
      intact. The antiviral efficacy of REP 2165 has been shown to be comparable to REP 2139 in a
      pre-clinical model of HBV infection with significantly less accumulation in the liver. As
      such, REP 2165 is expected to have comparable antiviral efficacy in human patients with
      reduced liver accumulation during treatment.

      HBsAg has important immunosuppressive effects in HBV infection which have been shown to block
      both adaptive and innate immune processes. Removal of HBsAg from the blood of patients
      removes this immunosuppressive effect.

      Thus, an important additional effect of removal of HBsAg from the blood is to greatly enhance
      the effect of pegylated interferon alpha 2a. It is expected that elimination of serum HBsAg
      with REP 2139-Mg or REP 2165-Mg will lead to creation of a favourable immunological
      activation in the absence of HBsAg, appearance of free anti-HBs, clearance of HBV virions in
      the blood and synergistic immunostimulation with conventional dosing of pegylated interferon
      alpha-2a and improved control of HBV infection in the presence of tenofovir disoproxil
      fumarate (TDF). All patients will receive 24 weeks of monotherapy with TDF prior to entry
      into experimental or active comparator arms.
    

Intervention name(s): REP 2139-Mg; Pegasys; Viread; REP 2165-Mg
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): REP 2139-Mg = magnesium chelate complex of REP 2139; immunotherapy; HBV RT polymerase inhibitor; REP 2165-Mg = magnesium chelate complex of REP 2165
Other intervention name(s): not availalble; pegylated interferon alpha-2a; tenofovir disoproxil fumarate; unaivalable
Intervention MeSH terms: Interferons; Tenofovir; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a; REP 2139
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment