The nucleic acid-based polymer REP 2139, used first as
monotherapy then combined with pegylated interferon, reduced hepatitis B
surface antigen (HBsAg) levels, lowered hepatitis delta viral load and
increased anti-HBs antibody titres, according to findings from a small phase 2
study presented on Sunday at the 2015 AASLD
Liver Meeting in San Francisco, USA. Participants fell into two distinct groups,
with half being partial responders and half full responders.
Antiviral therapy using nucleoside/nucleotide analogues
such as entecavir (Baraclude) or
tenofovir (Viread) is the mainstay of
treatment for chronic hepatitis B. While these
drugs can effectively suppress hepatitis B virus (HBV) replication during
therapy they usually do not lead to a cure, as indicated by HBsAg loss
and development of anti-HBs antibodies (seroconversion).
Hepatitis delta (HDV) is a small virus that can only
replicate in the presence of HBV; in turn, HDV appears to 'repress' HBV
replication. There is no standard treatment for HDV, although interferon
promotes immune responses against both viruses. Liver disease progression is
more rapid and complications are more common in people with HBV and HDV co-infection
compared to those with HBV alone.
Montreal-based Replicor
is developing nucleic acid polymers (NAPs) that interfere with assembly
and release of HBV subviral particles, thereby lowering HBsAg levels in the
blood. Because HBsAg is required for hepatitis delta assembly, reducing HBsAg
also suppresses HDV levels. Early studies showed that REP 2139 reduced serum
HBsAg levels and HDV viral load.
At the Liver Meeting, Replicor researchers presented
an update on the safety and efficacy of REP 2139 assessed first as monotherapy
and then with pegylated interferon in a phase 2 trial (NCT02233075) of Caucasian patients with chronic HBV and HDV
co-infection. (A previous study showed promising results in Asian patients with
HBV mono-infection.)
This analysis includes 12 participants in
Moldova who had baseline serum HBsAg > 1000 U/ml, were hepatitis B 'e'
antigen (HBeAg) negative and had mild to moderate liver fibrosis but no
cirrhosis.
Participants first received 500mg once-weekly
intravenous infusions of REP 2139-Ca (calcium chelate complex) for 15 weeks.
This was followed by REP 2139-Ca at a reduced dose of 250mg once weekly for
another 15 weeks plus 180 mcg/week pegylated interferon alfa-2a (Pegasys) continued for 48 weeks.
All participants experienced declines in serum
HBsAg during REP 2139-Ca monotherapy, though responses were highly variable.
Patients fell into two groups, with half considered partial responders and the
other half full responders with larger HBsAg decreases (falling to < 1 IU/ml).
HBsAg levels remained stable or continued to
decrease after adding pegylated interferon. After discontinuing REP-2139,
partial responders saw an increase in serum HBsAg, while full responders
maintained low levels.
All 12 patients experienced HDV RNA reductions –
again quite variable – with 10 achieving undetectable levels. In most patients,
reduced HDV levels led to rising HBV viral load, which the researchers
attributed to 'de-repression'. HBV DNA fell again after adding interferon and
discontinuing REP 2139.
Most participants had increased anti-HBs
antibody levels during REP 2139 monotherapy. Full responders experienced
substantial further anti-HBs increases after adding pegylated interferon, while
the partial responders did not.
Full responders experienced ALT and AST
increases – including some with substantial 'flares' – after adding pegylated
interferon, while partial responders did not see this effect.
REP 2139-Ca was generally safe and
well-tolerated. The most common adverse event was mild to moderate transient
intravenous infusion reactions (fever, headache, injection site redness or
itchiness) attributed to the IV tubing.
"REP 2139-Ca is able to simultaneously
reduce HBsAg and HDV RNA in patients with chronic HBV/HDV coinfection,"
the researchers concluded. "Increased anti-HBs production and/or liver
flares correlated with the start of [pegylated interferon] exposure appears to
be related to the extent of clearance of serum HBsAg."
The findings, they said, indicate that NAPs seem
to have distinct antiviral activity against HDV in addition to blocking HBV
subviral particles.
"Longer combination treatment with
immunotherapy will likely result in a higher proportion of patients with a full
HBsAg response (<1 IU/ml)," they suggested. "NAP-based antiviral
therapy may become an important new treatment option for patients with HBV/HDV
coinfection."