Substantial inhibition of viral production can be achieved in patients with chronic hepatitis B virus (HBV) infection by a novel mechanism — inhibition of encapsidation of pregenomic HBV RNA with NVR 3-778, an antiviral agent targeted to the HBV core protein — according to a phase 1 study published in Gastroenterology.1

Chronic viral hepatitis due to HBV is a leading cause of premature death worldwide,2,3 thus, improved treatment options are needed to reduce the risk for severe liver disease and death from HBV. NVR 3-778 is an orally bioavailable, first-in-class HBV capsid assembly modulator that can inhibit HBV replication.1 Researchers conducted a proof-of-concept study to examine the safety, pharmacokinetics, and antiviral activity of NVR 3-778 in 73 hepatitis B e-antigen (HBeAg)-positive patients with chronic HBV infection without cirrhosis. 

In this 2-part study, patients were randomly assigned to receive oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1000 mg twice daily ) or placebo for 4 weeks. Some patients received combination treatment with pegylated interferon (pegIFN) and NVR 3-778 (600 mg twice daily) or pegIFN with placebo. They found that NVR 3-778 was well tolerated and demonstrated antiviral activity. NVR 3-778 reduced serum levels of HBV DNA and HBV RNA, which occurred to the greatest extent in combination with pegIFN. These observed reductions in HBV RNA confirm the novel mechanism of NVR 3-778.

The study authors concluded that “NVR 3-778 treatment for 28 days, up to a dose of 1000 mg BD, was generally well tolerated.”1 They added that, “Substantial and correlated reductions in serum HBV DNA and HBV RNA levels were observed consistently with the higher-dose cohorts, and were notably greatest for combination treatment with NVR 3-778 and pegIFN.”

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References

  1. Yuen MF, Gane EJ, Kim DJ, et al. Antiviral activity, safety, and pharmacokinetics of capsid assembly modulator NVR 3-778 in patients with chronic HBV infection [published online January 5, 2019]. Gastroenterology. doi: 10.1053/j.gastro.2018.12.023
  2. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546-1555.
  3. Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet. 2016;388:1081-1088.