Treatment that interferes with viral assembly shows promise for hepatitis B

JNJ-56136379, an experimental drug that interferes with assembly of the hepatitis B virus (HBV) capsid, demonstrated potent antiviral activity in an early clinical trial, researchers reported at the recent 2017 AASLD Liver Meeting in Washington, DC.

Nucleoside/nucleotide antivirals such as tenofovir DF (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication during therapy, but they usually do not lead to a cure – as indicated by hepatitis B surface antigen clearance and anti-HBs antibody seroconversion – and scientists are working on novel therapies that may offer better options.

JNJ-56136379 (or JNJ-379 for short), being developed by Janssen (a Johnson & Johnson company), binds to the HBV core protein and appears to have a dual mode of action. It interferes with both disassembly of the HBV capsid when the virus enters cells, which is necessary to access viral genetic material for replication, as well as assembly of capsids to encase genetic material of new virions, resulting in the production of non-functional viral particles.

Fabien Zoulim of Lyon University and INSERM in France and colleagues evaluated the safety, tolerability, pharmacokinetics and antiviral activity of multiple doses of JNJ-379 in people with chronic hepatitis B, after the new agent was shown to be well tolerated at doses up to 600mg in healthy HBV-negative volunteers.

The phase 1b portion of this ongoing randomised, placebo-controlled study enrolled people with chronic HBV infection who had not previously been treated with nucleoside/nucleotide analogues and had HBV DNA above 2000 IU/ml. People with liver cirrhosis were excluded.

Participants in two different cohorts in Europe were assigned to receive JNJ-379 at doses of 25mg or 75mg, or a placebo, once daily for 28 days. The 25mg cohort started with a 100mg loading dose on the first day.

The 25mg and 75mg cohorts each included 12 participants. Most were men, two-thirds were white and the median age was about 38 years. Half of the 25mg cohort and three-quarters in the 75mg were hepatitis B 'e' antigen (HBeAg)-negative – an easier-to-treat group relative to HBeAg-positive people. A majority had HBV genotype D.

The 75mg dose of JNJ-379 produced a "more pronounced and consistent" decline in HBV DNA, the researchers reported. At the end of 28 days of treatment, average reductions in HBV DNA were 2.16 log₁₀ in the 25mg cohort and 2.89 log₁₀ in the 75mg cohort. Three people in the 75mg group – but none in the 25mg group – reached an undetectable viral load. HBV RNA levels declined by 2.30 log₁₀ in the 25mg cohort and 1.85 log₁₀ in the 75mg cohort. There were no notable changes in HBsAg or HBeAg levels.

JNJ-379 was generally safe and well tolerated, with no serious adverse events or treatment discontinuations due to adverse events. Overall adverse events occurred with similar frequency in the 25mg and 75mg groups. One person developed a high amylase (pancreatic enzyme) level and one had a severe ALT elevation, both of which returned to normal.

Based on the good safety profile so far, the researchers will evaluate higher doses of JNJ-379. A cohort now enrolling in Europe and Asia will receive 150mg, according to the poster.