Experimental siRNA therapy lowers HBsAg levels in people with hepatitis B

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ARC-520, a novel therapy using short interfering RNA, appeared safe and was associated with a reduction in hepatitis B surface antigen levels in people with chronic hepatitis B taking entecavir, according to phase 2a study results reported at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting in Boston, in November.

Antiviral therapy using nucleoside/nucleotide analogues like tenofovir (Viread) or entecavir (Baraclude) is the mainstay of chronic hepatitis B treatment. Although these drugs can effectively suppress hepatitis B virus (HBV) replication during therapy, they typically do not eradicate the virus and do not lead to serological response, or HBV antigen loss or antibody seroconversion.

Man-Fung Yuen of the University of Hong Kong and colleagues tested a new type of hepatitis B treatment using short interfering RNA (siRNA). These are small pieces of double-stranded ribonucleic acid (RNA) that can ‘silence’ or block expression of messenger RNA.


hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.



A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.


Lowest of a series of measurements. For example, an individual’s CD4 nadir is their lowest ever measured CD4 count.


Something the immune system can recognise as 'foreign' and attack.

ARC-520 is a novel liver-targeted siRNA therapy designed to interfere with HBV replication and protein production. Previous studies have shown that it decreased expression of viral proteins and reduced the number of viral particles in HBV mouse models and in an HBV-infected chimpanzee.

Viral proteins – in particular hepatitis B ‘e’ antigen (HBeAg) and hepatitis B surface antigen (HBsAg) – have been implicated in immune tolerance, sustained infection and disease progression, the researchers noted as background. Therapies targeting viral proteins might enable immune reconstitution, thereby promoting HBsAg clearance.

Yuen's group conducted a phase 2a trial to test the efficacy of single doses of ARC-520 in reducing HBsAg levels in HBeAg-negative people with chronic hepatitis B taking long-term entecavir.

This randomised, double-blind, dose-ranging study enrolled 24 adults with hepatitis B at two centres. They were randomly assigned to receive single intravenous injections of ARC-520 at escalating doses of 1, 2 or 3 mg/kg, or else placebo, preceded by an oral antihistamine (Benadryl) as a precaution against hypersensitivity reactions. They continued to take entecavir throughout the study.

The researchers reported data from 8 people in Cohort 1 (1mg/kg) and 8 in Cohort 2 (2mg/kg), evaluated through post-dose day 85. A majority (63%) were men, all were of Chinese ethnicity and ages ranged from 37 to 59 years. Cohort 3 is ongoing and remains blinded.

ARC-520 recipients experienced greater decreases in serum HBsAg compared to placebo recipients, and HBsAg levels declined more with the 2mg/kg dose than with the lower dose.

ARC-520 activity was assessed by measuring percent change in HBsAg from the baseline level. In Cohort 1, participants in the study receiving ARC-520 had an average nadir decline, or maximum decrease, of -39% (range -22% to -57%) at post-dose day 43, with a mean change of -31% at day 85 (range -14% to -39%),

For participants receiving ARC-520 in Cohort 2, the average nadir reduction was -51% (range -46% to -59%) at post-dose day 57, with a mean change of -22% at day 85 (range -7% to -40%). In this cohort, the percent reduction in HBsAg was statistically significant compared to placebo through day 43.

A previous phase 1 study found that ARC-520 had a favourable safety profile in 54 healthy HBV-uninfected people receiving doses of 0.01 to 4mg/kg. There were no apparent dose-limiting toxicities. One person taking ARC-520 experienced flushing and one developed hives; however, no one pre-treated with oral antihistamine showed evidence of hypersensitivity. There were no observed differences in adverse events, vital signs, physical exams or electrocardiograms between ARC-520 and placebo recipients.

In the phase 2a study, ARC-520 again appeared to be safe and well-tolerated at the doses tested. There were no serious adverse events, no dose-limiting toxicities and no early discontinuations due to adverse events. All reported adverse events were deemed unrelated or unlikely to be related to the study drug. Abnormal laboratory values were uncommon.

"A single injection of ARC-520 resulted in significant reduction in HBsAg for up to 43 days," the researchers concluded. "This is the first time that a reduction in HBsAg mediated through RNA interference has been shown in chronic HBV patients."


Yuen M et al. Phase II, dose-ranging study of ARC-520, a siRNA-based therapeutic, in patients with chronic hepatitis B virus. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract LB-21, 2014.