- Presentation at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) demonstrates reduction of key HBV antigens and DNA, and evidence of immune reactivation in a chimpanzee with chronic HBV infection
PASADENA, Calif.--(BUSINESS WIRE)--November 04, 2013--
Arrowhead Research Corporation (NASDAQ:ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today announced that it presented new data on ARC-520, its clinical candidate for the treatment of chronic hepatitis B virus, at the 2013 AASLD Annual Meeting. The data demonstrate that intravenous administration of two doses (2 mg/kg, 3 mg/kg) of ARC-520 in a chimpanzee chronically infected with HBV, resulted in substantial and sustained reductions in HBV DNA, HBeAg, and HBsAg, which did not return to baseline until study day 43, 43, and 71 respectively. In addition, an increase in serum alanine transaminase (ALT) occurred 4 weeks after the last dose, coincident with the nadir of circulating HBsAg. This is suggestive of a therapeutic immunological flare, which is thought to be part of a cascade that under chronic therapy may lead to HBsAg seroconversion and functional cure. Robert E. Lanford, Ph.D., of the Texas Biomedical Research Institute where the study was conducted, presented these data and the poster was selected as a Presidential Poster of Distinction indicating that it was in the top 10% of all abstracts selected for poster presentation.
"This study would have been important if ARC-520 just demonstrated safe and effective HBsAg reduction because this is thought to be a necessary step in achieving a functional cure," said Dr. Lanford. "What is really exciting about these data, however, is that we appear to have seen immune de-repression, the next step toward HBsAg seroconversion and functional cure. The timing of the ALT rise and associated increases in key chemokine/cytokine mRNAs suggest that they were related to the therapy-induced reduction in circulating HBsAg and represented an immunological event."
The study was a proof-of-concept antiviral efficacy trial for ARC-520, which is composed of 2 cholesterol-conjugated siRNAs and the hepatocyte-targeted membrane-lytic Dynamic Polyconjugate (DPC) delivery vehicle. It was conducted at the Texas Biomedical Research Institute in a single chimpanzee chronically infected with HBV since 1979 (chimpanzee 4x0139; genotype B; viral load 1.3x10(10) GE/ml; HBsAg 824 g/ml). Activity was monitored using serum levels of HBV DNA, HBeAg, and HBsAg. Safety was monitored using CBC, blood chemistries, and serum levels of 39 cytokines and chemokines. Liver histology, viral antigens, and host transcripts were monitored in the liver.
Arrowhead previously reported initial data through day 29 of this study. The animal was monitored at additional time points through day 85 to assess duration of effect for ARC-520 and other outcome measures. HBV DNA levels dropped by 17-fold by day 4, exhibited a 36-fold decline following the second dose, and returned to baseline by day 43. HBeAg levels declined by more than one log by day 4 and returned to baseline by day 43. HBsAg levels declined gradually reaching a 5.2-fold reduction on day 29 and did not return to baseline until day 71. HBsAg is a serum lipoprotein complex and has a significant half-life in circulation, thus declines for this marker were more gradual but also more sustained. An increase in ALT was observed near the HBsAg nadir.
"This is an important addition to our data set and a milestone for the development plan of ARC-520," said Christopher Anzalone, Ph.D., Arrowhead's President and CEO. "We successfully completed enrollment in a Phase 1 clinical study in healthy volunteers with initial data indicating that ARC-520 is generally safe and well tolerated in humans. We will be filing with Hong Kong regulatory authorities this quarter to enable a Phase 2a study in patients with chronic HBV infection."
Arrowhead also recently presented a poster at the 2013 International Meeting on Molecular Biology of Hepatitis B Viruses. The data presented indicate that treatment with ARC-520 in combination with entecavir appears to be additive and possibly synergistic. These results support plans to initiate a Phase 2a study of ARC-520 in combination with entecavir, pending regulatory approval.
Copies of both poster presentations can be found on the Presentations and Events page of the Arrowhead website at www.arrowheadresearch.com/presentations.