Effective inhibition of cccDNA derived mRNA/viral antigens and tolerability with ARC-520

Abstract

BACKGROUND: ARC-520, an RNA interference drug, targets ccc-DNA-derived mRNA in chronic hepatitis B patients (CHB); herein we report tolerability/activity in normal healthy volunteers (NHV) and CHB. METHODS: 54 NHV (36 ARC-520, 18 placebo) and 58 CHB (48 ARC-520, 10 placebo) were included. At entry, 32 of 38 HBeAg-neg and 14 of 20 HBeAg-pos CHB had taken entecavir for mean 5 years (range 2–8) and continued throughout the study. NHV and CHB received 0.01 to 4 mg/kg IV ARC-520 or placebo; CHB had viral parameters measured. RESULTS: ARC-520 therapy was well tolerated—67 % NHV (placebo or ARC-520) and 23 % CHB reported a mild or moderate adverse event (AE) with no AE rated serious, severe, or causing withdrawal. A modest occurrence of abnormal laboratory tests was observed. Two NHV showed moderate hypersensitivity reactions (urticarial rash, flushing) during infusion. After addition of pretreatment oral antihistamine, no hypersensitivity reactions were seen. ARC-520 reduced viral antigens with qHBeAg best reduction of 1.7 log (mean max 1.2 log) following a single 4 mg/kg dose. In treatment-naïve CHB, best qHBsAg reductions of 1.9 log (mean max 1.3 log) in HBeAg-pos and 0.8 log (mean max 0.3 log) in HBeAg-neg were observed. Similar reductions in HB core related antigen were observed where measurable. CONCLUSIONS: (1) ARC-520 effectively inhibited cccDNA-derived mRNA with protein reductions up to 1.9 logs (99 %) (2) ARC-520 was well tolerated and hypersensitivity symptoms were controlled by antihistamine pretreatment. (3) This is the first time direct antiviral effects on HBeAg and HBsAg have been demonstrated.