RNA interference therapy lowers viral biomarker in people with hepatitis B

14 Dec 2017 Liz Highleyman
Originally published on www.infohep.org

ARB-1467, a novel type of treatment for hepatitis B, reduced levels of hepatitis B surface antigen (HBsAg) when used alone, and it may play a role in combination therapy to cure the infection, researchers reported at the recent 2017 AASLD Liver Meeting in Washington, DC.

Current standard therapy for hepatitis B virus (HBV) using nucleoside/nucleotide antivirals like tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication over the long term but usually does not lead to a cure, as indicated by hepatitis B surface antigen (HBsAg) clearance and development of anti-HBs antibodies.

ARB-1467, being developed by Arbutus Biopharma, consists of synthetic small interfering RNAs directed against HBV messenger RNAs, targeting three different sites in the HBV genome.

Dr Kosh Agarwal of the Institute of Liver Studies at King’s College Hospital in London and colleagues evaluated the safety, pharmacokinetics and antiviral activity of multiple doses of ARB-1467 in a phase 2 clinical trial.

The study included 36 people with chronic hepatitis B on stable treatment with tenofovir DF or entecavir. A majority were men, they were predominantly white or Asian and the median age was approximately 45 years. About 80% were hepatitis B 'e' antigen (HBeAg)-negative, a majority had HBV genotype C and about half had undetectable HBV DNA at baseline.

Participants were randomly assigned to receive ARB-1467 or placebo at doses of 0.2 or 0.4 mg/kg given by intravenous infusion once a month or biweekly for 12 weeks. Participants in cohort 4, all of whom were HBeAg-negative, started with 0.4 mg/kg biweekly dosing and switched to once-monthly dosing for up to a year if they had HBsAg < 1000 IU/ml and at least a 1 log10 decline by week 12.

Everyone treated with ARB-1467 saw a reduction in HBsAg from baseline. People who received the drug biweekly had larger HBsAg declines than those who received once-monthly infusions, and the 0.4 mg/kg dose worked better than the 0.2 mg/kg dose. Most people with declines of more than 1 log10 had undetectable HBV RNA at baseline.

HBV RNA levels decreased modestly in all groups (by about 0.5 log10) and hepatitis B core-related antigen (HBcrAg) levels did not change much in any group. These measures were not correlated with HBsAg decline.

The researchers also presented more detailed results for the HBsAg-negative participants in cohort 4. One of the 12 participants in this group dropped out early due to adverse events. Seven of the 11 remaining people (64%) were classified as responders and switched from biweekly to monthly dosing.

The largest HBsAg decline was 2.7 log10, and five people in this group reached levels below 50 IU/ml. However, none achieved HBsAg clearance. Having a lower baseline HBsAg level and the IL28b CC gene variation (associated with interferon signaling) predicted larger HBsAg declines on ARB-1467.

Treatment was generally safe and well tolerated, with no drug-related serious adverse events and two discontinuations due to adverse events (one with hepatitis E super-infection and one with a mild infusion reaction, joint pain and hair loss). ALT values remained normal throughout treatment.

The researchers concluded that monthly dosing does not appear to be sufficient to maintain or improve initial HBsAg reductions achieved with biweekly administration, and suggested that combination therapy with other therapies and longer treatment duration may be needed for a functional cure of hepatitis B.

A forthcoming trial will evaluate ARB-1467 in combination with tenofovir and pegylated interferon, according to an Arbutus press release.