Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial
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
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−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 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 . Elebsiran plus PEG-IFNα improved hepatitis B surface antigen (HBsAg) loss rates compared with PEG-IFNα alone in patients with chronic hepatitis B virus infection. Furthermore, prior response to the BRII-179 vaccine was associated with higher HBsAg clearance, suggesting its potential as a predictive tool for identifying patients more likely to benefit from therapies.