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EASL 2016: Core Inhibitor NVR 3-778 Plus Pegylated Interferon Inhibits Hepatitis B Activity

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 European Association for the Study of the Liver's International Liver Congress (EASL 2016) this 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 cell's nucleus, leading to persistent infection. Depletion of HBV cccDNA is likely to prove critical in attempts to either eradicate HBV completely or to achieve a functional cure.

NVR 3-778 appears to inhibit HBV by multiple mechanisms, offering a new approach to hepatitis B treatment. Current therapy using nucleoside/nucleotide analog 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 anti-HBs antibodies.

Researchers 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 from 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.

This study enrolled adults with HBeAg-positive chronic hepatitis B and baseline HBV DNA above 20,000 IU/mL. All but 3 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 coinfected with HIV, hepatitis C, or hepatitis delta were excluded.

Participants in the first 4 sequential cohorts were randomly assigned to receive NVR 3-778 monotherapy at doses of 100, 200, or 400 mg once-daily, or 600 mg twice-daily, for 28 days; in each cohort 8-10 people received active NVR 3-778 capsules while 2 received a placebo. Another cohort was added to test 1000 mg twice-daily NVR 3-778 monotherapy and is currently ongoing. Two additional cohorts of 10 people each were randomized to receive either 600 mg twice-daily NVR 3-778 or placebo plus once-weekly injections of 180 mcg pegylated interferon alfa-2a.

At last year's AASLD Liver Meeting Yuen's team first presented results from the 4 NVR 3-778 monotherapy cohorts. At the latest conference he also presented findings from the 2 cohorts that received pegylated interferon.

Results

• In the monotherapy arms, the 100, 200, and 400 mg once-daily doses of NVR 3-778 produced small reductions in HBV DNA (<0.5 log IU/mL).
• Raising the dose to 600 mg twice-daily, however, produced a mean reduction of 1.72 log IU/mL.
• HBV DNA fell by a mean 1.97 log IU/mL in the group receiving NVR 3-778 plus pegylated interferon, compared to a 1.06 log drop in the pegylated interferon plus placebo arm.
• HBV RNA levels also fell, by a mean of 1.51 log in the NVR 3-778 plus pegylated interferon arm, 0.73 log in the interferon plus placebo arm, and 0.82 in the 600 mg monotherapy arm.
• Early reductions in serum HBeAg levels were also observed, falling by around 0.2 to 0.3 log, with the largest decline seen in the 600 mg NVR 3-778 monotherapy arm.
• Changes in HBsAg levels were negligible, as would be expected with such a short treatment duration.
• Safety and tolerability were satisfactoryat 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 1 serious adverse event deemed possibly treatment-related, a severe skin rash in the 100 mg monotherapy arm.

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.

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 clearance.

Planned Phase 2 trials will evaluate longer treatment with NVR 3-778 in combination with pegylated interferon and first-line nucleoside/nucleotide drugs.

4/26/16

Reference

M-F Yuen, DJ Kim, F Weilert, et al. NVR 3-778, a first-in-class HBV core inhibitor, alone and in combination with peg-interferon (pegIFN), in treatment- naive HBeAg-positive patients: early reductions in HBV DNA and HBeAg. Abstract LBO6.

Other Source

EASL. Potential first-in-class treatment is well-tolerated in patients with chronic Hepatitis B. Press release. April 16, 2016.