The nucleic acid
polymers REP 2139 and REP 2165 led to hepatitis B surface antigen (HBsAg)
reduction or clearance when combined with tenofovir and pegylated interferon,
according to early results from a small study presented as a late-breaker at
the 2016 AASLD Liver Meeting this month in Boston. This combination may potentially
enable functional control of hepatitis B if confirmed in larger studies.
Over years or decades
chronic hepatitis B virus (HBV) infection can lead to advanced liver disease
including cirrhosis and liver cancer. Antiviral therapy using nucleoside/nucleotide
analogues such as entecavir (Baraclude)
or tenofovir disoproxil fumarate (Viread)
is the mainstay of treatment for chronic hepatitis B. While these drugs can suppress HBV replication during therapy, and can
thereby reduce the risk of liver disease progression, they usually do
not lead to a cure – as indicated by HBsAg loss and anti-HBs antibody
seroconversion – and long-term treatment is generally needed.
Researchers are therefore looking at other approaches
to more curative hepatitis B treatment. Montreal-based Replicor, Inc. is developing nucleic acid polymers (NAPs) that
interfere with the assembly and block the release of HBV sub-viral particles
from infected hepatocytes. Unlike nucleoside/nucleotide analogues, NAPs do not
directly target fully formed HBV virions.
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
A shortage of neutrophils, a type of white blood
cell that fights bacterial infections.
A low level of platelets in the blood. In people with hepatitis, this may be due to cirrhosis or interferon treatment.
enzyme that can be measured in a blood sample that indicates the health of the
Andrew Vaillant of Replicor presented the latest
findings from a study of the safety and efficacy of a pair of NAPs – REP 2139
and REP 2165 – used in combination with tenofovir DF and pegylated interferon
for the treatment of hepatitis B 'e' antigen (HBeAg)-negative chronic hepatitis.
Blocking release of HBV sub-viral particles leads to
lower HBsAg levels in the blood, Dr Vaillant noted as background. This in turn reduces HBsAg-mediated
immune suppression, and the resulting stronger immune response can lead to
liver enzyme flares and eventual establishment of hepatitis B control in some
individuals. This may also enhance the effectiveness of immunotherapy such as
Early studies showed
that NAPs reduced HBsAg and HBV DNA levels in serum as well as HBV
covalently closed circular DNA (cccDNA) in the liver, an intermediate form that
persists in the cell nucleus and presents a barrier to a cure. At last year's
EASL International Liver Congress Dr Vaillant reported that REP 2139, lowered levels of HBsAg, HBV DNA and
hepatitis delta, a small virus that can only replicate in the presence of HBV.
Study REP 401 evaluated REP 2139 and the related drug
REP 2165, which appears to have similar antiviral activity but with less accumulation in the liver.
Investigators used REP 2139 and REP 2165 formulated as magnesium chelate
complexes (known as REP 2139-Mg and REP 2165-Mg) to improve their administration
This open-label study enrolled 40 people with chronic hepatitis B
in Moldova. Most were men and the mean age was about 38 years. They were
HBeAg-negative, had baseline serum HBsAg > 1000 U/ml and HBV DNA > 7500
copies/ml, and most had HBV genotype D. They did not have cirrhosis and had mostly
mild to moderate liver fibrosis (stage F0-F2) and did not have co-infection with with
hepatitis delta, hepatitis C or HIV.
All participants started taking once-daily oral
tenofovir DF (300mg) for 24 weeks. They were then randomly assigned to two
treatment arms. Those in the experimental arm stayed on tenofovir DF and
received weekly intravenous infusions of either REP 2139-Mg or REP 2165-Mg (250mg)
plus weekly injections of pegylated interferon alfa-2a (180 mcg/week) for 48
weeks. The control arm stayed on tenofovir DF and added pegylated interferon
alone; after 24 weeks on dual therapy those with less than a 3 log10
decline in HBsAg also added REP 2139-Mg or REP 2165-Mg.
The primary study endpoints were serum HBsAg
reduction, appearance of anti-HBs antibodies and functional control after
stopping treatment, defined as HBsAg < 1 IU/ml and HBV DNA < 1000 copies/ml
for at least six months. Dr Vaillant presented data for 29 people followed
for more than 12 weeks after randomisation, including nine who received REP 2139
and nine who got REP 2165.
All participants experienced gradual declines in serum
HBV DNA after starting tenofovir DF. HBsAg levels did not decline during
treatment with tenofovir DF alone, or with tenofovir plus pegylated interferon,
but dropped steeply after adding REP 2139 or 2165. All nine patients who
received REP 2139 had a > 1 log10 decrease in HBsAg, as did six of
the nine who received REP 2165. Three people taking REP 2139 and two taking REP
2165 saw their HBsAg levels fall below the lower limit of quantification. REP
2165 had antiviral activity similar to that of REP 2139 despite more rapid
Increases in anti-HBs
antibodies correlated with the extent of HBsAg reduction after participants added
either REP 2139 or REP 2615.
Treatment with REP 2139 or EP 2165 was generally safe
and well tolerated. Serum alanine and aspartate transaminase (ALT and AST)
levels rose in most people after adding REP 2139 or REP 2165 plus pegylated
interferon, and a few saw increases on pegylated interferon alone. These ALT
and AST increases correlated with HBsAg reduction and mostly resolved with
continued therapy. Liver function was otherwise normal during these ALT and AST
flares, with bilirubin, albumin and blood clotting time remaining stable.
Kidney function also remained generally stable in all
treatment arms. As expected, pegylated interferon was associated with adverse
events including weakness, neutropenia (low white blood cells) and
thrombocytopenia (low platelets), but this did not differ based on whether REP
2139 and REP 2165 were also used. Administration of REP 2139 and REP 2165 was
generally asymptomatic, though one individual had infusion reactions after the
20th dose of REP 2165-Mg. There was a single drug-related serious adverse event,
profound weakness attributed to pegylated interferon.
concluded that NAP therapy in combination with tenofovir DF and pegylated
interferon is associated with multi-log reduction or clearance of serum HBsAg,
increases in serum anti-HBs antibodies, and increased incidence and magnitude
of serum transaminase flares that were otherwise asymptomatic and self
said that the ALT and AST flares – markers of liver inflammation – were not
due to liver toxicity, but rather were "therapeutic," indicating that
the decline in HBsAg was likely leading to strengthened immune response against