Hepatitis B core inhibitor NVR 3-778 inhibits viral replication in early clinical trial

Novira 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. 

The researchers 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.

These preclinical data paved the way for early clinical trials on NVR 3-778 in humans.

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 significant rash.

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 future.

"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 concluded.