Johnson & Johnson’s short interfering RNA treatment for
hepatitis B resulted in sustained reductions in hepatitis B surface antigen
when combined with nucleoside analogue drugs, Professor Edward Gane of Auckland
City Hospital, New Zealand, told the Digital International Liver Congress this
He was presenting results of a phase 2a study of the
combination of JNJ-3989 and a nucleoside or nucleotide analogue.
Hepatitis B is a chronic infection. Current treatments can
suppress viral replication and reduce liver damage but cannot cure the
Nucleoside or nucleotide analogues (NRTIs) block hepatitis B
virus replication but do not block the production of hepatitis B surface
antigen nor prevent the replenishment of the pool of cccDNA in hepatocytes
which supports viral replication if NRTI therapy is stopped. NRTI treatment
must continue indefinitely to control hepatitis B replication.
Combining NRTIs with antivirals which directly block viral
entry into hepatocytes, or prevent the production of viral proteins, is judged
more likely to deliver a functional cure for hepatitis B infection – viral suppression
without the need for treatment.
Achieving a functional cure is likely to require a combination of drugs. “Functional
cure” means that all antigens (e.g. HBsAg, HBeAg) and the HBV DNA of the virus
disappear from the blood, and only antibodies remain. The cccDNA of the
hepatitis B virus however remains in the liver cells. So far, it is not
possible to also eliminate hepatitis B cccDNA from liver cells, which would be closer
to a “sterilizing cure”.
Arrowhead and Johnson & Johnson are developing a small
interfering RNA agent, JNJ-3989, as an antiviral for use in combination with an
The small interfering RNA (siRNA) binds to messenger RNA
(mRNA), preventing transcription of mRNA involved in the production of viral
proteins, including HBV polymerase and hepatitis B surface antigen.
JNJ-3989 is given by subcutaneous injection, in combination
with daily oral dosing of an NRTI (tenofovir or entecavir). Preliminary results
from this phase 2 study, reported in 2019, showed that three doses of JNJ-3989
given at days 0, 28 and 56 were well tolerated and resulted in reductions in
hepatitis B surface antigen, HBeAg, hepatitis B RNA and hepatitis B core
antigen 8 weeks after the third injection.
Professor Edward Gane presented longer-term follow-up from
the phase 2 study at the International Liver Congress.
The AROHBV1001 phase 2a open-label study recruited people positive
or negative for HBeAg, both NRTI-experienced and NRTRI-naïve. Four groups of
eight were assigned to ascending doses of JNJ-3989 (100mg-400mg) and two
groups of four (one NRTI-naïve, one NRTI-experienced) were assigned to a 300mg
This analysis reviewed hepatitis B surface antigen responses
48 weeks after the last JNJ-3989 dose. Sustained response was defined as a >
1 log10 IU/ml reduction in hepatitis B surface antigen at week 48.
Dosing groups were predominantly male and Asian, and the
majority in groups 1-4 were HBeAg negative. Eighty per cent of all study
participants were NRTI-experienced.
The mean hepatitis B surface antigen titre at baseline was
approximately 4 log IU/ml. The mean nadir reduction in hepatitis B surface
antigen ranged from -1.72 log10 IU/ml in the 100mg group to -2.04 log10 IU/ml in
the 300mg group. Thirty-four out of 40 participants achieved a nadir reduction
of >1 log10 IU/ml and 15 out of 38 (34%) achieved a sustained response at 48
weeks. The mean reduction at 48 weeks in the sustained response group was -1.74 log10 IU/ml.
Hepatitis B surface antigen sustained responders also had
sustained reductions in HBV RNA, HBeAg and HBcoreAg.
The investigational treatment continued to be well tolerated
with no new drug-related adverse events reported beyond day 85. Adverse events
consisted of mild injection site reactions (7), mild muscle pain (2) and
abdominal pain (2), 2 mild cases of hyperbilirubinemia and 1 severe creatine
kinase elevation (likely due to taking creatine health supplements prior to
study entry). No grade 2 ALT elevations were observed during the study,
suggesting that JNJ-3989 does not have an adverse effect on the liver.
Short-term siRNA treatment can result in sustained hepatitis
B surface antigen reduction, the study investigators concluded, supporting future
studies of 48 weeks of JNJ-3989 and NRTIs, with or without JNJ-6379, a capsid