1 Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
2 Eugastro Gmbh, Leipzig, Germany.
3 Seoul National University Hospital, Seoul, Republic of Korea.
4 Yonsei University College of Medicine, Seoul, Republic of Korea.
5 Pusan National University and Medical Research Institute, Busan, Republic of Korea.
6 Gachon University Gil Hospital, Incheon, Republic of Korea.
7 The Chinese University of Hong Kong, Hong Kong, China.
8 Pusan National University Yangsan Hospital, Yangsan-si Gyeongnam, Republic of Korea.
9 Universitaetsklinikum Wuerzburg, Wuerzburg, Germany.
10 Medizinische Hochschule Hannover, Hannover, Germany.
11 IFI Institute at Asklepios Klinik St. Georg, Hamburg, Germany.
12 Arrowhead Pharmaceuticals, Inc, Pasadena, California, USA.
13 Unit of Infectious Diseases and Hepatology, University of Parma, Parma, Italy.
14 Victorian Infectious Diseases Reference Laboratory, Victoria, Australia.
15 Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, California, USA.
ARC-520, the first RNA interference (RNAi) therapeutic was designed to reduce all RNA transcripts derived from cccDNA, leading to a reduction in viral antigens and HBV DNA. 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, multi-center studies in nucleoside/nucleotide (NUC) experienced patients with hepatitis B e antigen negative (E-neg) or 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 PEIU/mL in the low dose and high dose ARC-520 groups respectively. ARC-520 was well tolerated, with only two SAEs of pyrexia possibly related to study drug observed. In conclusion, 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.