Experimental
drugs that interfere with hepatitis B virus (HBV) capsid assembly continue to
show promise as a new approach to antiviral treatment, according to research presented at the AASLD Liver Meeting last month in San Francisco.
Nucleoside/nucleotide antivirals such as tenofovir DF
(Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can
suppress HBV replication indefinitely during long-term therapy. They
seldom lead to a cure, however, and researchers are exploring new approaches
that might be more effective alone or in combination.
Capsid assembly modulators (CAMs) interfere with the HBV core protein, which
plays a role in packaging viral genetic material into a nucleocapsid shell. This leads to the production of defective virus that is unable
to replicate. CAMs also inhibit formation of HBV covalently closed
circular DNA (cccDNA), probably by interfering with capsid disassembly, an
early step in viral replication.
JNJ-56136379 (JNJ-6379 for short) is a CAM being developed
by Janssen. Fabien Zoulim of INSERM Cancer Research Institute in Lyons, France, reported findings from a
study evaluating the antiviral activity, safety, pharmacokinetics of JNJ-6379
given for 4 weeks, followed by 8 weeks of follow-up, in people being treated
for hepatitis B for the first time.
This phase 1b trial enrolled 48
people with chronic HBV infection and HBV DNA levels above 2000 IU/ml. More than 80%
were men, most were white and the median age was approximately 40 years. About
a quarter were hepatitis B 'e' antigen (HBeAg) positive. They mostly had absent
or mild liver fibrosis (stage F0-F1); none had advanced fibrosis or cirrhosis.
Participants were assigned to receive JNJ-6379 at
doses of 25mg (after a 100mg loading dose), 75mg, 150mg, 250mg
or a placebo once daily for 4 weeks.
At this year's EASL International Liver
Congress in April, Zoulim reported early results from the first three groups.
After 4 weeks of treatment, HBV DNA declined by -2.16, -2.89 and -2.70 log10
in the 25mg, 150mg and 75mg dose groups, respectively. At The Liver Meeting, he reported that HBV
DNA also fell by -2.70 log10 in the 250mg group
at 4 weeks. At the end of treatment, 38% in the 75mg and 150mg groups and 56%
in the 250mg group had undetectable HBV DNA.
Viral levels began to rise after stopping
treatment. Those in the 25mg group saw their HBV DNA return almost to the
baseline level. The rise was slower in the intermediate dose groups and the
level remained low in the highest dose group. At the end of 8 weeks of
follow-up (4 on and 4 off treatment), HBV DNA levels were -0.27, -1.71, -1.51
and -2.19 log10 below baseline in the respective dose groups.
HBV RNA levels showed the opposite
pattern, falling by -2.30, -1.85, -1.83 and 1.43 log10 in the
respective groups. At the end of treatment, 75% in the 75mg and 150mg groups
and 89% in the 250mg group had undetectable HBV RNA, but the number of patients
with RNA data was small.
Viral DNA and RNA levels changed little in
the placebo group (-0.11 and -0.02 log10, respectively). After 4
weeks of treatment, no placebo recipients had HBV DNA below the level of
quantification, though 36% had undetectable HBV RNA
No notable changes in hepatitis B surface
antigen (HBsAg) or HBeAg levels were observed, which Zoulim said was to be expected
with such a short treatment period.
Treatment was generally well tolerated.
Three people had severe (grade 3-4) adverse events. One person in the 150mg
group stopped treatment early due to liver enzyme elevation.
JNJ-6379 "demonstrated potent
antiviral activity by reducing HBV DNA and HBV RNA," the researchers
concluded.
Noting that there was a limited increase
in antiviral activity at higher doses, Jordan Feld of University Health Network
in Toronto, who presented a 'debrief' of viral hepatitis studies at The Liver
Meeting, suggested that a higher dose may be needed to disrupt formed capsids and
prevent replenishment of cccDNA.
Another research team presented findings
from a phase 1b trial of another core inhibitor CAM known as ABI-H0731. This
study mostly enrolled Asian men. Again, participants were assigned to receive
one of four doses of the drug or a placebo for 4 weeks.
Man-Fung Yuen of Queen Mary Hospital in Hong
Kong reported that HBV DNA decreased by about -1.5, about -2.0 and nearly -3.0 log10 , respectively, in the 100mg, 200mg and 300mg
dose groups. Those who were HBeAg negative saw larger declines than those who
were HBeAg positive. Although there were only two evaluable patients in the
400mg group, they had an impressive mean -3.9 log10
drop. Here, HBV RNA reductions corresponded with HBV
DNA declines. Again no significant changes in HBeAg or HBsAg levels were seen.
Yuen's team likewise concluded that ABI-H0731
conferred "potent antiviral activity" and warranted further study.
Many experts believe that a combination
approach will be needed to achieve a functional cure for hepatitis B. Based on
these findings, phase 2 trials of JNJ-6379
and ABI-H0731 plus nucleoside/nucleotide analogue antivirals are
currently underway.