RNA Interference Therapy With ARC‐520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients With Chronic Hepatitis B Infection

BACKGROUND AND AIMS: ARC‐520, the first an RNA interference (RNAi) therapeutic, was designed to reduce all RNA transcripts derived from covalently closed circular DNA, leading to a reduction in viral antigens and hepatitis B virus (HBV) DNA. APPROACH AND RESULTS: We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC‐520 compared to placebo (PBO) in two randomized, multicenter studies in nucleoside/nucleotide analogue reverse‐transcriptase inhibitor (NUC)–experienced patients with hepatitis B early antigen (HBeAg)–negative (E‐neg) or HBeAg‐positive (E‐pos) disease. A total of 58 E‐neg and 32 E‐pos patients were enrolled and received four monthly doses of PBO (n = 20 E‐neg, 11 E‐pos), 1 mg/kg ARC‐520 (n = 17 E‐neg, 10 E‐pos), or 2 mg/kg ARC‐520 (n = 21 E‐neg, 11 E‐pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC‐520 dose were compared to PBO. Both E‐neg and E‐pos high‐dose groups significantly reduced HBsAg compared to PBO, with mean reductions of 0.38 and 0.54 log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and >85 days after the last dose in E‐neg and E‐pos patients, respectively. The low‐dose groups did not reach statistical significance in either study. E‐pos patients showed a dose‐dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 log Paul Ehrlich IUs/mL in the low‐dose and high dose ARC‐520 groups respectively. ARC‐520 was well tolerated, with only two serious adverse events of pyrexia possibly related to study drug observed. CONCLUSIONS: ARC‐520 was active in both E‐neg and E‐pos, NUC‐experienced HBV patients; but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin.