Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial

作者：Man‐Fung Yuen, Jeong Heo, Jeong-Won Jang, Jung‐Hwan Yoon, Young-Oh Kweon, Sung Jae Park, Yvonne Tami, Shihyun You, Phillip Yates, Tao Yu, Jennifer Cremer, Fiona Campbell, Robert C. Elston, Dickens Theodore, Melanie Paff, C. Frank Bennett, T. Jesse Kwoh · 发表于：Nature Medicine · 年份：2021 · DOI：10.1038/s41591-021-01513-4 · 被引用次数：158 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Animal Virus Infections Studies

Abstract Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml −1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA...