Therapeutic Safety and Efficacy of REP 2139 (REP 9AC') in HBV 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 and post-entry antiviral
      activity against duck hepatitis B virus (DHBV) infection. REP 2055 has been shown to have
      potent therapeutic effect against established DHBV infection in vivo

      REP 2055 was additionally shown to have significant antiviral effects in patients with
      chronic HBV infection in the previous REP 101 study. REP 2139 is a version of REP 2055
      designed for improved administration tolerability and stability.

      The safety and antiviral activity REP 2139, first in monotherapy and then in combination with
      immunotherapy in patients with chronic HBV infection will be assessed in the REP 102
      protocol.
    

Detailed description: 
      Chronic hepatitis B is a long term condition caused by infection of the body with the
      hepatitis B virus (HBV). This infection often results 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 from the blood and the liver and develops a durable immunological control
      of subsequent HBV infection). However, these drugs do significantly decrease the risk of
      liver damage and liver cancer arising from the presence of a chronic liver infection by
      slowing or stopping the production of infectious virus. Thus the primary problem associated
      with currently available drugs is the lack of clearance of the virus from the hepatocytes
      which necessitates long term treatment with these drugs. There is clearly a need to identify
      new drugs that can benefit patients with chronic hepatitis B infections. Nucleic acid-based
      polymers (NAPs) are a new class of broad-spectrum antiviral compounds which act against HBV
      infection by blocking the release of the surface antigen protein (HBsAg) from infected
      hepatocytes. In the human patients in the REP 101 protocol, the previous NAP clinical
      candidate, REP 9AC (REP 2055), rapidly induced pronounced reductions in or clearance of serum
      HBsAg in 7 out of 8 patients. HBsAg is the major immunoinhibitory mechanism by which HBV
      maintains its chronicity and by reducing or eliminating HBsAg from the blood, REP 9AC appears
      able to elicit restoration of durable immunological responses in patients capable of clearing
      the HBV infection. The performance of REP 9AC in providing sustained virologic responses
      (SVRs) in patients with chronic HBV infection appeared to be far superior than any compound
      currently approved for the treatment of HBV infection

      REP 9AC' (REP 2139) is a modified version of its predecessor, REP 9AC (REP 2055). Both are
      40mer phosphorothioate oligonucleotides comprised of alternating adenosine and cytidine
      nucleotides and in the case of REP 9AC, has been shown to have low toxicity and to be highly
      effective in treating hepatitis B infection in human patients. The modifications in REP 9AC'
      significantly improve the stability and reduce the pro-inflammatory activity of REP 9AC'
      compared to that of REP 9AC while retaining all the antiviral activity found in REP 9AC. Both
      these modifications (5-methylation of cytosines and 2' O methylation of the ribose sugar in
      each nucleotide) are naturally occurring modifications in human nucleic acid and are known to
      be well tolerated in clinical trials. It is expected that REP 9AC' will be able to achieve a
      more robust antiviral activity in patients with chronic HBV with significantly lower dosing
      requirements and fewer side effects than REP 9AC.

      Current interim data analysis from the still ongoing REP 101 assessing the activity of REP
      9AC in patients with chronic HBV infection indicates the following:

        1. REP 9AC exposure in eight patients has been generally well tolerated at doses up to
           600mg / week and 400mg / day (for seven continuous days). Administration related side
           effects include mild to moderate pro-inflammatory reactions during the drug
           administration (itching and fever) which disappear after drug administration is
           complete. Chronic side effects include mild elevations in blood anticoagulation
           (international normalized ratio ~1.5) and serum hypocalcemia (which is easily mitigated
           with a mineral supplement).

        2. REP 9AC has achieved serum HBsAg reduction or clearance in all patients compliant with
           the proscribed dosing regimen (7 out of 7).

        3. In these seven patients, 5 have demonstrated restoration of at least a partial
           immunological control of their infection (appearance of serum anti-HBs and the
           establishment of a lower serum HBV DNA setpoint).

        4. Of the five patients achieving having an immunological response, three have achieved a
           SVR off treatment with as few as 20 weeks of REP 9AC treatment with complete and durable
           immunological control over their infection for 18, 12 and 10.5 months.

        5. Suboptimal stability of REP 9AC is a likely factor impairing the performance of the
           drug.

      This proposed study is designed to demonstrate that REP 9AC' 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 and then in combination
      with immunotherapy.

      NAPs: Replicor's technology utilizes the novel properties of NAPs 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 first generation clinical candidate, 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.

      NAPs (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 be well tolerated in human patients in several clinical
      trials.

      REPLICor has validated the compatibility of the modifications in REP 9AC' with the antiviral
      activity present in NAPs indirectly: the 2'O methyl sugar modification was found to not
      affect the antiviral activity of NAPs against duck hepatitis B virus in vivo and further
      shown to substantially improve the stability of NAPs to nuclease degradation and
      substantially reduce their immunoreactivity in human peripheral blood mononuclear cells . The
      5'methylation of cytosine was shown not to affect target interaction in cell free interaction
      assays and is well known to mitigate the immunoreactivity of nucleic acids.

      It is now a widely held notion that any successful outcome in the treatment of chronic HBV
      must involve immunostimulation in order to catalyze restoration of the appropriate immune
      responses (both adaptive and innate) in order to achieve durable control over HBV infection
      after therapy. The results from REP 101 protocol suggest that elimination of serum HBsAg
      removes the chronic immunosuppression mediated by this protein. However there is a
      heterogeneous immunological response to HBsAg reduction / clearance in the patients treated
      to date (as measured by serum HBV DNA decline): only about 40% of patients appear to exhibit
      a strong immunological response after the reduction / removal of serum HBsAg . This
      observation strongly suggests that while HBsAg suppression is essential for establishing
      durable immunological control, specific immunostimulation may also be required in many
      patients in order for them to achieve durable immunological control .

      Thymosin alpha 1 (Zadaxin™) is synthetically prepared thymosin alpha 1 polypeptide (28 amino
      acids, molecular weight 3108) which is identical to the naturally occurring thymosin alpha 1
      present in humans. Thymosin alpha 1 shares homology with the interferon alpha family of
      peptides but unlike interferon alpha, Zadaxin administration in human subjects is not
      accompanied by any significant side effects. More importantly, Zadaxin administration with
      other proinflammatory compounds (like interferon alpha) does not alter the side effect
      profiles of those compounds.

      Zadaxin shares many of the immunostimulatory properties of interferon alpha in that it is
      able to stimulate the production of several cytokines important in reestablishing an immune
      response capable of controlling the HBV infection. Zadaxin is also able to stimulate the
      production of natural killer, CD4 and CD8 cells all known to be correlated with the
      establishment of a durable immunological control of HBV infection.

      In the treatment of chronic HBV in the clinic, Zadaxin monotherapy is able to achieve HBeAg
      and HBV DNA seroclearance in 30-50% of patients which is comparable or better than that
      achievable with interferon alpha. More important is the consistent observation that the
      proportion of patients achieving HBV DNA seroclearance off therapy continually increases (an
      effect not observed with interferon alpha).

      Based on the very low side effect profile of Zadaxin (both as a monotherapy and in
      combination with interferon alpha and HBV polymerase inhibitors) and its clear ability to
      stimulate functional and durable immune response and control of HBV in patients with chronic
      HBV infections, the investigators strongly suspect that Zadaxin add-on therapy in patients
      currently receiving REP 9AC' will be safe and may have a synergistic effect on the ability of
      patients to achieve durable immunological control, thus greatly increasing the proportion of
      patients achieving durable immunological control with REP 9AC' - Zadaxin therapy compared to
      either therapy alone.

      It may be possible that the immunostimulation provided by Zadaxin™ may not provide a strong
      or broad enough immunostimulatory effect to provide an additive or synergistic antiviral
      response from the patient's immune system while on REP 9AC' therapy. Since Pegasys™ is a much
      stronger immunostimulatory drug but having significant side effects, dosing with this
      compound will be slowly escalated each week to a full dose (180 ug once weekly) providing no
      grade 3 adverse events are observed.
    

Intervention name(s): REP 2139-Ca; Zadaxin; Pegasys
Intervention type(s): Drug; Drug; Drug
Intervention description(s): REP 2139-Ca is administered weekly at 250 or 500mg doses by slow IV infusion.; Zadaxin is administered twice weekly (1.6mg) by subcutaneous injection; Pegasys in administered once weekly by subcutaneous injection with dose escalation to 180ug / week.
Other intervention name(s): thymosin alpha 1; pegylated interferon alpha-2a
Intervention MeSH terms: Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a; REP 2139; Thymalfasin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment