Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial

作者：Grace Lai‐Hung Wong, Man‐Fung Yuen, Bingliang Lin, Mark W. Douglas, Peng Hu, Qing Xie, Fangfang Lv, Won Young Tak, Apinya Leerapun, Dong Joon Kim, Pisit Tangkijvanich, Young‐Suk Lim, Chia‐Yen Dai, James O’Beirne, Martin Weltman, Suparat Khemnark, Teerha Piratvisuth, Witsarut Manasirisuk, Xinyue Chen, Chun‐Jen Liu, Jeong Heo, Joo‐Ho Lee, Junqi Niu, Rahul Kumar, Rajneesh Kumar, Chong Zhu, Ke Cao, Alex Tian, Xiaofei Chen, Qing Zhu, David J. Margolis, Jidong Jia, Zhi Hong · 发表于：Nature Medicine · 年份：2025 · DOI：10.1038/s41591-025-04049-z · 被引用次数：12 · 研究领域：Hepatitis B Virus Studies、RNA Interference and Gene Delivery、Hepatitis C virus research

Functional cure is a goal for the treatment of chronic hepatitis B virus (HBV) infection; however, it is infrequently achieved with currently approved treatments. Here we provide a randomized evaluation of the small interfering RNA elebsiran, in combination with pegylated interferon alfa (PEG-IFNα), compared with PEG-IFNα monotherapy. In addition, this study evaluates the potential role of the HBV therapeutic vaccine BRII-179 in identifying immunologically responsive patients and improving hepatitis B surface antigen (HBsAg) loss rates. In part I (cohorts 1–3), virally suppressed participants with chronic HBV infection naive to BRII-179 were randomized 1:1:1 to receive 48 weekly doses of PEG-IFNα alone or in combination with 13 doses of elebsiran (200 mg or 100 mg) administered every 4 weeks. In part II (cohort 4), participants who had previously received 9 doses of elebsiran and BRII-179 in a prospective study (BRII-179-835-001) were categorized as BRII-179 anti-HBs responders or nonresponders based on their peak hepatitis B surface antibody (anti-HBs) levels (≥10 IU l−1 or <10 IU l−1, respectively) and subsequently received 13 doses of elebsiran 100 mg every 4 weeks plus 48 weekly doses of PEG-IFNα. Primary endpoints were HBsAg loss at the end of treatment (EOT) and 24 weeks post-EOT. In part I, at 24 weeks post-EOT, HBsAg loss was observed in 4 out of 19 (21.1%) participants receiving elebsiran 200 mg plus PEG-IFNα, 6 out of 18 (33.3%) participants receiving elebsiran 100 ...