NVR 3-778, an experimental drug that interferes
with hepatitis B virus (HBV) capsid assembly, led to reductions in HBV DNA, HBV
RNA and hepatitis B 'e' antigen (HBeAg), showing greater activity when combined
with pegylated interferon, researchers reported at the 2016 International
Liver Congress last month in Barcelona.
NVR 3-778, being developed by Novira Therapeutics, is a first-in-class
small molecule that directly targets the HBV core protein, which plays key
roles in viral replication and persistence. It is responsible for assembly of
the viral nucleocapsid and enables replenishment of HBV cccDNA, which is incorporated into the cellular nucleus, leading to persistent infection. Depletion of HBV ccDNA is likely to prove critical in attempts either to cure hepatitis B completely or to achieve a functional cure, whereby hepatitis B virus replication is permanently controlled without treatment.
NVR 3-778 appears to
inhibit HBV by multiple mechanisms, offering a new approach to hepatitis B
treatment. Current therapy using nucleoside/nucleotide analogue antivirals or
interferon can suppress HBV replication long-term, but seldom leads to a cure
as indicated by hepatitis B surface antigen (HBsAg) loss and development of
previously demonstrated that NVR 3-778 causes mis-assembly of the HBV core
protein in vitro. Treating
HBV-producing cells with NVR 3-778 blocked encapsidation of viral genetic
material, preventing the production and release of functional infectious virus.
Prior research showed that NVR 3-778 blocked replication of various
HBV strains in a laboratory study. In genetically engineered mice with human
hepatocytes, combining NVR 3-778 with pegylated interferon led to greater antiviral
activity than either drug alone. An early human trial showed that NVR 3-778 was generally safe and well tolerated.
Man-Fung Yuen of the
University of Hong Kong and colleagues conducted a phase 1b trial of the safety
and efficacy of NVR 3-778, used alone and with pegylated interferon, in chronic
hepatitis B patients.
study enrolled adults with HBeAg-positive chronic hepatitis B and baseline HBV
DNA above 20,000 IU/ml. All but three were men, the median age was
approximately 40 years, a majority were Chinese and most had HBV genotypes B or
C. They had normal or modestly elevated alanine aminotransferase (ALT), no
liver cirrhosis and had not previously been treated for hepatitis B. People co-infected
with HIV, hepatitis C or hepatitis delta were excluded.
in the first four sequential cohorts were randomly assigned to receive NVR
3-778 monotherapy at doses of 100, 200 or 400mg once daily, or 600mg
twice daily, for 28 days; in each cohort eight to ten people received active
NVR 3-778 capsules while two received a placebo. Another cohort was added to
test 1000mg twice-daily NVR 3-778 monotherapy and is currently ongoing. Two
additional cohorts of ten people each were randomised to receive either 600mg
twice-daily NVR 3-778 or placebo plus once-weekly injections of 180mcg
pegylated interferon alfa-2a.
year's AASLD Liver Meeting, Dr Yuen's team first presented
results from the four NVR 3-778 monotherapy cohorts. At the latest conference he also presented findings from the two cohorts
that received pegylated interferon.
In the monotherapy arms, the 100,
200, and 400mg once-daily doses of NVR 3-778 produced small reductions in HBV
DNA (< 0.5 log10 IU/ml). But raising the dose to 600mg twice daily
produced a mean reduction of 1.72 log10.
HBV DNA fell by a mean 1.97 log10 IU/ml in the group receiving NVR 3-778 plus pegylated
interferon, compared to a 1.06 log10 drop
in the pegylated interferon plus placebo arm.
HBV RNA levels also fell, by a mean
of 1.51 log10 in the NVR 3-778 plus pegylated
interferon arm, 0.73 log10 in
the interferon plus placebo arm, and 0.8210 in
the 600mg monotherapy arm.
Early reductions in serum HBeAg levels were also
observed, falling by around 0.2 to 0.3 log10, with
the largest decline seen in the 600mg NVR 3-778 monotherapy arm. However, changes
in HBsAg levels were negligible, as would be expected with such a short
Safety and tolerability were satisfactory at all dose levels, with no early discontinuations. Adverse
events and laboratory abnormalities were generally mild and mostly not
attributed to the study drug. There was one serious
adverse event deemed possibly treatment-related, a severe skin rash in the 100mg
Dr Yuen said at an EASL press briefing
that NVR 3-778 and pegylated interferon showed synergistic activity when used
together, with the nearly 2-log reduction in HBV DNA being "very
impressive" for just 28 days of therapy.
Dr Yuen explained that nucleoside/nucleotide antivirals usually do not
reduce HBV RNA in addition to DNA, but acknowledged that the significance of
HBV RNA reduction is not clear. He added that the mechanisms leading to HBsAg
loss are also not well understood, but suggested it is possible that inhibiting
the HBV core protein allows an immune response that leads to 's' antigen
Planned phase 2 trials will evaluate longer treatment
with NVR 3-778 in combination with pegylated interferon and first-line nucleoside/nucleotide