TITLE: ARC-520 RNAi therapeutic reduces hepatitis B virus DNA, S antigen and e antigen in a chimpanzee with a very high viral titer
AUTHORS (FIRST NAME, LAST NAME): Robert E. Lanford1, Christine I. Wooddell2, Deborah Chavez1, Claudia Oropeza3, Qili Chu2, Holly L. Hamilton2, Alan McLachlan3, Bruce Given4, Christopher R. Anzalone4, David L. Lewis2
Institutional Author(s):
INSTITUTIONS (ALL): 1. Texas Biomedical Research Institute, San Antonio, TX, United States.
2. Arrowhead Madison, Arrowhead Research Corporation, Madison, WI, United States.
3. Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, United States.
4. Corporate Office, Arrowhead Research Corporation, Pasadena, CA, United States.
ABSTRACT BODY: Chronic hepatitis B virus (HBV) infection is a major disease world-wide for which there remains an unmet medical need. Current therapies have little effect on the viral proteins that allow sustained infection and progression of disease, and prevent the patient from mounting an effective immune response. We are developing a small interfering RNA (siRNA)-based therapeutic named ARC-520 that is designed to decrease viral protein load by the mechanism of RNA interference (RNAi). We have shown that a single intravenous injection of ARC-520 results in multi-log repression of viral RNA, proteins and DNA with long duration of effect (more than one month) in transient and transgenic mouse models of chronic HBV infection, without toxicity. Here, we present studies that demonstrate dose-dependent reduction of HBV DNA in serum and liver, HBV transcripts in liver, HBsAg, HBeAg and core antigen from single or multiple doses of ARC-520 in mice. Multiple doses of ARC-520 enabled an extended duration of effect. Recently we extended our investigations of ARC-520 to treatment of a chimpanzee chronically infected with HBV since 1979. This animal was 36-years old, weighed 51 kg and had a very high viral titer of HBV genotype B (1E+10 GE/ml serum). A single intravenous injection of 2 mg/kg of ARC-520 was well-tolerated and resulted in decreases in serum levels of HBsAg, HBeAg and HBV DNA. A subsequent injection of 3 mg/kg two weeks after the first injection correlated with increased pharmacological effect, giving 81-96% reductions in these HBV parameters at nadir. These reductions were similar in magnitude and duration of effect to those observed in the mouse HBV models receiving similar doses. The efficacy and safety of ARC-520 in a large primate demonstrate its promise as a new class of therapeutic for patients chronically infected with HBV.