The nucleic acid-based
polymer REP 2139-Ca lowered hepatitis B surface antigen (HBsAg) levels and
significantly reduced hepatitis B and hepatitis delta viral loads when combined
with immunotherapy, according to presentations at the European Association
for the Study of the Liver (EASL) 50th International Liver Congress
last month in Vienna, Austria.
years or decades, chronic hepatitis B virus (HBV) infection can lead to advanced
liver disease including cirrhosis and liver cancer. Disease progression is more
rapid and complications are more common in people with hepatitis
delta virus (HDV) co-infection, a small virus that can only replicate in the presence of
therapy using nucleoside/nucleotide analogues such as entecavir (Baraclude) or tenofovir (Viread) is the mainstay of chronic
hepatitis B treatment. While these drugs can
effectively suppress HBV replication during therapy, they usually do not lead to a cure, as
indicated by HBsAg loss and development of anti-HBs antibodies (seroconversion).
There is no standard treatment for hepatitis D, although interferon can
stimulate the body's immune response to both HBV and HDV.
Chemical "messengers" exchanged between immune cells that affect the function of
the immune system. Interleukins such as IL-2 are a particular type of
Researchers are working on another treatment approach using
nucleic acid polymers (NAPs), oligonucleotides with broad-spectrum antiviral
activity. Montreal-based Replicor is developing NAPs for the treatment of
both hepatitis B and hepatitis delta. According to the company, NAPs have a safety advantage
because their activity is not sequence-dependent, so they can be
engineered to retain antiviral activity without undesirable side-effects.
Preclinical research showed that NAPs target both
entry and post-entry steps of the viral lifecycle. They block HBV and HDV entry
into hepatocytes (liver cells) and also interfere with assembly and release of
HBV subviral particles, thereby lowering HBsAg levels in the blood. As HBsAg is
required for HDV assembly, reducing HBsAg also suppresses HDV. NAPs do not
directly target replication of HBV virions (complete viral particles) like
existing antiviral agents.
Early studies found that REP2139-Ca lowered HBsAg
levels and HBV and HDV blood viral load, 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.
Replicor chief scientific officer Andrew Vaillant
presented late-breaking finding from a phase 2 study (REP 301) evaluating the
safety and efficacy of REP 2139-Ca in Caucasian patients with chronic HBV/HDV
co-infection. A previous study (REP 102) tested REP 2139-Ca in Asian patients
with HBV mono-infection.
Vaillant's study included 12 Caucasian people with HBV/HDV
co-infection in Moldova. At the start of treatment, they had serum HBsAg
>1000 U/ml, were hepatitis B 'e' antigen (HBeAg)-negative and had
mild-to-moderate liver fibrosis (no cirrhosis).
REP 2139-Ca was administered first as monotherapy,
500mg once-weekly intravenous infusions for 15 weeks. This was followed by REP
2139-Ca at a dose of 250mg once-weekly for another 15 weeks in combination with
pegylated interferon alfa-2a (180 mcg/week), which was continued for 48 weeks.
Virus levels (HBV DNA, HDV RNA, HBsAg and anti-HBs
antibodies) were measured every two weeks. Vaillant reported results obtained
between week 20 and 25, while participants were still taking both REP 2139-Ca
and interferon; monitoring will continue through 24 weeks post-treatment.
All participants experienced reductions in serum HBsAg
during REP 2139-Ca monotherapy, but they fell into two groups. One group saw
decreases of around 1-2 log10, while the second group saw drops of
4-5 log10 or more. HBsAg levels remained stable or continued to
decrease after adding pegylated interferon.
Anti-HBs antibody levels remained undetectable or rose
slightly in most patients, but the individuals who experienced the greatest
HBsAg declines saw substantial antibody gains, which accelerated after the
addition of interferon.
HDV RNA levels also fell across the board, with
considerable variability between patients. Individuals with the greatest HBsAg
declines saw the largest and most rapid drops in HDV viral load. Decreases
ranged up to 7 log10 and five people reached undetectable HDV RNA.
But even some people with smaller HBsAg declines eventually experienced
substantial HDV RNA reductions, suggesting that REP 2139-Ca may have multiple
antiviral effects against HDV, Vaillant said.
Treatment with REP 2139-Ca was generally safe and
well-tolerated. During the monotherapy phase, before adding interferon, all
adverse events were mild to moderate and were associated with intravenous
infusion (fever, headache, injection site redness). These side-effects
typically became less frequent as treatment progressed and resolved after
completion of the infusions.
"REP 2139-Ca is able to simultaneously reduce
HBsAg and HDV RNA in patients with chronic HBV/HDV coinfection," the
researchers summarised. "[The] pharmacologic effect on serum HBsAg
observed in Asian patients is replicated in Caucasian patients." Combing REP
2139-Ca with pegylated interferon "may provide additional productive
antiviral response," they added.
"NAP-based antiviral therapy may become an
important new treatment option for patients with HBV/HDV coinfection,"
At an earlier session, Louis Jansen from Academic
Medical Centre in Amsterdam presented findings from the aforementioned phase 2
study of Asian chronic hepatitis B patients treated with REP 2139-Ca plus immunotherapy. This study included 12 HBV monoinfected participants who were
HBeAg-positive and had detectable HBV DNA (mean 6.7 log) at study entry, were previously
untreated for hepatitis B and
did not have cirrhosis.
Participants were initially
treated with 500mg once-weekly REP 2139-Ca monotherapy for 20-24 weeks. People
who were good HBsAg responders then added either pegylated interferon or thymosin alfa-1 (Zadaxin) for
13-26 weeks, while non-responders started entecavir.
A majority of participants saw declines in HBsAg, HBV DNA and HBV RNA
levels after starting REP 2139-Ca monotherapy. Nine participants
were considered responders, having at least a 2-log10 decline in HBV
RNA and large declines in HBsAg levels. At week 20-24 eight of these patients had
undetectable HBV RNA. Four of the nine responders experienced HBsAg loss and
anti-HBs antibody seroconversion during post-treatment follow-up – far higher
than the response rates seen in people treated with antivirals alone or
antivirals plus pegylated interferon.
In contrast, the three people without substantial
declines in HBV RNA at week 20-24 showed no notable reduction in HBsAg or HBV
DNA levels. They then started entecavir and their HBV DNA levels declined
significantly, but the antiviral "didn't do much for [HBV] RNA levels," Jansen said.
"Treatment of chronic hepatitis B patients with
REP 2139-Ca resulted in a pronounced decline of serum HBV RNA in nine of 12
patients," the researchers concluded. "In three of 12 patients
(non-responders), HBV RNA levels were unaffected, both before and after
treatment with entecavir."
A retrospective analysis from the same study looked at changes in cytokines, or immune cell
chemical messengers, and found evidence that REP 2139-Ca may help restore
immune responses against HBV.
Vaillant indicated that
studies of REP 2139-Ca are ongoing. He noted that the drug has poor oral
bioavailability, but Replicor expects it can be given by once-weekly
subcutaneous injection rather than the two-hour infusions used in these trials.
The company is also testing another NAP candidate, REP 2165.