Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial.
Journal
Nature medicine
Journal Volume
32
Journal Issue
1
Start Page
151
End Page
159
ISSN
1546-170X
Date Issued
2026-01
Author(s)
Wong, Grace Lai-Hung
Yuen, Man-Fung
Lin, Bingliang
Douglas, Mark W
Hu, Peng
Xie, Qing
Lv, Fangfang
Tak, Won Young
Leerapun, Apinya
Kim, Dong Joon
Tangkijvanich, Pisit
Lim, Young-Suk
Dai, Chia-Yen
O'Beirne, James
Weltman, Martin
Khemnark, Suparat
Piratvisuth, Teerha
Manasirisuk, Witsarut
Chen, Xinyue
Heo, Jeong
Lee, Jooho
Niu, Junqi
Kumar, Rahul
Kumar, Rajneesh
Zhu, Chong
Cao, Ke
Tian, Alex
Chen, Xiaofei
Zhu, Qing
Margolis, David
Jia, Jidong
Hong, Zhi
Abstract
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 or <10 IU l, 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 mg plus PEG-IFNα and 1 out of 18 (5.6%) participants receiving PEG-IFNα monotherapy. In part II, HBsAg loss was observed in 9 out of 31 (29.0%) participants at 24 weeks post-EOT, with a higher response among BRII-179 anti-HBs responders (8 out of 19 participants, 42.1%) compared with nonresponders (1 out of 12 participants, 8.3%). Elebsiran and PEG-IFNα combination therapy was generally safe and well tolerated. These results demonstrate an additive benefit of elebsiran when combined with PEG-IFNα in achieving sustained HBsAg loss. Furthermore, the increased HBsAg loss rate in BRII-179 anti-HBs responders suggests that BRII-179 may be a valuable tool for immunological profiling to optimize curative outcomes in patients with HBV infection. ClinicalTrials.gov registration: NCT05970289 .
Type
journal article