First Clinical Trial Using “RNA Interference” for Hepatitis B Begins

—Christine. M. Kukka, Project Manager, HBV Advocate

A ground-breaking approach to hepatitis B treatment, which manipulates RNA messengers to halt viral replication, has begun its first human clinical trial. If successful, this approach would be a paradigm shift in treatment, possibly replacing interferon and antivirals.

In animal trials, reported in the May 2013 journal Molecular Therapy, RNA interference (RNAi) treatment reduced hepatitis B surface antigen (HBsAg) levels to undetectable within 24 hours in mice and the antigen remained undetectable for nearly a month.

RNAi treatment works by destroying or "silenc-ing" the molecular messengers that carry important genetic information to the hepatitis B virus (HBV) antigen/protein factories. Without the critical information that messenger RNA molecules carry, these antigen factories shut down and HBV reproduction declines dramatically.

Early RNAi research found that RNA silencing worked extremely well in the liver, but the challenge has been to create a formula and delivery system to target hepatitis B antigens in liver cells without affecting other important cells.

Arrowhead Research Corp. found that when the small RNA interrupters are linked to cholesterol, they target liver cells extremely well, and the addition of special polymers helps the gene-silencing process. Arrowhead designed an intravenous formula, called ARC-520, that is utilized in its Phase 1 trial.

The hope is that when the viral load is dramatically reduced, the body's immune system can gain the upper hand and eradicate the infection on its own.

In addition to its mouse trial, a similar trial involving an HBV-infected chimp with an extremely high viral load also led to rapid reduction in HBV DNA and a 90% reduction in another hepatitis B antigen—the hepatitis B "e" antigen (HBeAg).

The clinical trial of ARC-520 (which uses a Dynamic Polyconjugate delivery platform and includes two distinct RNA silencing agents that should shut down hepatitis B antigen reproduction) in humans is taking place in Melbourne, Australia. It is a randomized, double-blind, placebo-controlled trial. Each group of six healthy volunteers will receive either a placebo intravenous injection or a single dose of ARC-520.

The study, which concludes this fall, assesses the treatment's dosing safety and effectiveness. A Phase 2 trial involving people infected with HBV is scheduled to start in 2014 IN HONG KONG.
Source 1: "Hepatocyte-targeted RNAi Therapeutics for the Treatment of Chronic Hepatitis B Virus Infection," by Wooddell C, Rozema D, Hossbach M et al. Mol Ther. 2013 May; 21(5): 973–985. www.ncbi.nlm.nih.gov/pmc/articles/PMC3666629/

Source 2: ARC-520 Clinical trial information: Safety and Tolerability Study of ARC-520 in Healthy Volunteers : http://cirrus.mail-list.com/hepatitis-b/89653678.html

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