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

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<sup>-1</sup> or <10 IU l<sup>-1</sup>, 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 .

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Journal
Nature Medicine
Published
2025-11-07
DOI
https://doi.org/10.1038/s41591-025-04049-z
Citations
3
Primary Topic
Hepatitis B Virus Studies
Type
article
Field-Weighted Citation Impact
4.06

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article

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

Xinyue Chen, Suparat Khemnark, Bingliang Lin, Jidong Jia et al.
3 citations
Nature Medicine
Hepatitis B Virus Studies
4.06
article

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

Xinyue Chen, Suparat Khemnark, Bingliang Lin, Jidong Jia, Won Young Tak, Rahul Kumar, James P. O’Beirne, Martin Weltman, Ke Cao, Mark W. Douglas, Chia‐Yen Dai, Teerha Piratvisuth, Peng Hu, Jeong Heo, David J. Margolis, Alex Tian, Man‐Fung Yuen, Chun‐Jen Liu, Pisit Tangkijvanich, Young‐Suk Lim, Grace Lai–Hung Wong, Apinya Leerapun, Witsarut Manasirisuk, Xiaofei Chen, Qing Zhu, Dong Joon Kim, Rajneesh Kumar, Chong Zhu, Zhi Hong, Junqi Niu, Qing Xie, Joo‐Ho Lee, Fangfang Lv
article en
3 citations

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<sup>-1</sup> or <10 IU l<sup>-1</sup>, 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 .

Nature MedicineVol. 32(1)
Ulsan College (KR), Hallym University (KR), Kaohsiung Medical University (TW), Sun Yat-sen University (CN), Chulalongkorn University (TH), Chinese University of Hong Kong (HK), Capital Medical University (CN), Dalian Medical University (CN), Jilin University (CN), Singapore General Hospital (SG), Ruijin Hospital (CN), Kyungpook National University Hospital (KR), Asan Medical Center (KR), Nepean Hospital (AU), Changi General Hospital (SG), Sir Run Run Shaw Hospital (CN), Kaohsiung Medical University Chung-Ho Memorial Hospital (TW), Westmead Hospital (AU), University of Ulsan (KR), Second Affiliated Hospital of Chongqing Medical University (CN), Sunshine Coast University Hospital (AU), Bruker (China) (CN), Precision BioSciences (United States) (US), Songklanagarind Hospital (TH), Maharaj Nakorn Chiang Mai Hospital (TH), Bamrasnaradura Infectious Diseases Institute (TH), Pusan National University Hospital (KR), First Hospital of Jilin University (CN), National Taiwan University Hospital (TW), CHA University Bundang Medical Center (KR), System Biosciences (United States) (US), Westmead Institute for Medical Research (AU), Third Affiliated Hospital of Sun Yat-sen University (CN), Beijing YouAn Hospital (CN), Beijing Friendship Hospital (CN), CHA University (KR), Hallym University Chuncheon Sacred Heart Hospital (KR), Zhejiang University (CN), Chongqing Medical University (CN), University of Hong Kong (HK)
European Association for the Study of the Liver
Openalex Percentile: Top 5%
Hepatitis B Virus Studies
4.06
DOIOpen Access PDFOpenAlex
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