Chronic Hepatitis B Clinical Trial
Official title:
An Open-label, Randomized, Active Controlled, Parallel Comparison Study of the Safety and Efficacy of REP 2139-Mg in Combination With Pegasys® and Viread® and REP 2165-Mg in Combination With Pegasys® and Viread® in Patients With HBeAg Negative Chronic Hepatitis B
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.
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.
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