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AASLD 2014: Experimental siRNA Therapy Lowers HBsAg Levels in Hepatitis B Patients


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

Antiviral therapy using nucleoside/nucleotide analogs 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 from the University of Hong Kongand colleagues tested a new type of hepatitis B treatment using short interfering RNA (siRNA). siRNA are small pieces of double-stranded ribonucleic acid (RNA) that can "silence" or block expression of messenger RNA.

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 chronic hepatitis B patients taking long-term entecavir.

This randomized, double-blind, dose-ranging study enrolled 24 adult hepatitis B patients at 2 centers. 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 patients in Cohort 1 (1 mg/kg) and 8 in Cohort 2 (2 mg/kg), evaluated through post-dose day 85. A majority (63%) were men, all were of Chinese ethnicity, and ages raged from 37 to 59 years. Cohort 3 is ongoing and remains blinded.

ARC-520 activity was assessed by measuring percent change in HBsAg from the baseline level.


  • ARC-520 recipients experienced greater decreases in serum HBsAg compared to placebo recipients, and HBsAg levels declined more with the 2 mg/kg dose than with the lower dose.
  • In Cohort 1, patients 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%),
  • 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 Cohort 2, 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 favorable safety profile in 54 healthy HBV-uninfected people receiving doses of 0.01 to 4 mg/kg. There were no apparent dose-limiting toxicities. 1 person taking ARC-520 experienced flushing and 1 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."



M Yuen, H Chan, B Given, 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, November 7-12, 2014. AbstractLB-21.