Therapeutics' NVR 3-778, a novel drug that interferes with the hepatitis B
virus (HBV) core protein, blocked replication of various types of HBV in a
laboratory study and reduced HBV viral load with no apparent safety issues in
an early human trial, researchers reported at the 2015 AASLD
Liver Meeting last November in San Francisco.
NVR 3-778 is a
small molecule that directly targets the HBV core or capsid protein, which
plays a key role in viral replication and persistence. It appears to inhibit
the virus by multiple mechanisms and offers a new approach to hepatitis B
treatment, which currently relies on nucleoside/nucleotide analogue antivirals
or pegylated interferon.
Angela Lam of Novira
presented findings from preclinical research testing NVR 3-778 against
various HBV strains in a laboratory study, including wild-type virus,
nucleoside/nucleotide-resistant variants and representative strains from HBV genotypes
A through H.
found that NVR 3-778 induced faulty assembly of the HBV core protein, resulting
in dysfunctional capsid-like particles in
vitro. In HBV-producing cells treatment with NVR 3-778 blocked
encapsidation of viral genetic material. This in turn prevented production and release
of infectious virus containing HBV DNA or RNA. NVR 3-778 was active against
drug-resistant HBV variants and representatives of all HBV genotypes.
A related study – presented at the 2015 EASL International Liver Congress last April – tested NVR 3-778 in
genetically engineered mice with human hepatocytes (liver cells). In this study
NVR 3-778 demonstrated high intrinsic antiviral activity in mice
infected with HBV genotype C, with a HBV DNA reduction larger than that of
pegylated interferon and similar to that of the nucleoside analogue entecavir (Baraclude). Combining NVR 3-778 and
pegylated interferon led to greater antiviral activity than either drug alone,
with all five mice receiving this combination achieving undetectable HBV DNA.
Unlike entecavir, however, NVR 3-778 also reduced serum HBV RNA.
preclinical data paved the way for early clinical trials on NVR 3-778 in
At the 2014
Liver Meeting, Edward Gane of Auckland City Hospital presented findings from the first phase 1a
dose-ranging study, which evaluated the safety and pharmacokinetics of NVR
3-778 in healthy adult volunteers without hepatitis B. NVR 3-778 tolerance was
"satisfactory" at all doses tested. All participants completed the
study and there were no serious adverse events; side-effects were generally
mild and lab test abnormalities were infrequent.
At the more
recent Liver Meeting, Man-Fung Yuen of the
University of Hong Kong and colleagues presented a late-breaking poster
describing the safety, pharmacokinetics and antiviral efficacy of NVR
3-778 monotherapy in a phase 1b clinical study, the first in people with
chronic hepatitis B.
This proof-of-concept study enrolled 44 adults with
HBeAg-positive chronic hepatitis B, baseline HBV DNA levels above 20,000 IU/ml,
normal or modestly elevated ALT and no liver cirrhosis. All but three were men
and 26 were Chinese.
Participants in four sequential cohorts received NVR
3-778 capsules at escalating doses of 100, 200 or 400mg once-daily, or 600 mg
twice-daily, for 28 days. In each cohort 8 to 10 people received the active
drug while 2 received a placebo.
The 200 and 400mg once-daily doses of NVR 3-778
produced small reductions in HBV DNA (< 0.5 log10 IU/ml), but
tripling the dose to 600mg twice-daily produced a mean 28-day reduction of 1.72
log10 IU/ml (range 1.06 to 3.71 log10). Serum HBV RNA was
also reduced, by a mean 0.86 log10 IU/ml (range 0.16 to 1.50 log10)
Safety and tolerability of NVR 3-778 were again
"satisfactory" at all dose levels, with no early discontinuations or
serious adverse events. Adverse events and lab abnormalities were generally
mild and deemed not related to the study drug; the most common were upper
respiratory infections and sore throat. A single patient in the 100mg cohort
developed a serious rash on the hands and feet, but no one else had a
This study will go on to test higher doses of NVR
3-778, as well as the 600mg twice-daily dose in combination with pegylated
interferon. Combinations with nucleoside antivirals will be evaluated in the
"NVR 3-778 alone or in combination with current
HBV antivirals may contribute substantial efficacy by unique core-related
mechanisms to increase durable treatment response rates," the researchers