Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial
Wong GL, Yuen MF, Lin B, Douglas MW, Hu P, Xie Q, Lv F, Tak WY, Leerapun A, Kim DJ, Tangkijvanich P, Lim YS, Dai CY, O'Beirne J, Weltman M, Khemnark S, Piratvisuth T, Manasirisuk W, Chen X, Liu CJ, Heo J, Lee J, Niu J, Kumar R, Kumar R, Zhu C, Cao K, Tian A, Chen X, Zhu Q, Margolis D, Jia J, Hong Z.
- DOI
- 10.1038/s41591-025-04049-z
- Record issued
- 2026-08-10
- Engine
- 7.29.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/a8ae8df7-f8b5-41b3-8aea-70f88cfbe5f8 is authoritative.
How this rating was calculated
- ReportingData & code availability not met−0.5★
- ReportingKey resources partially met−0.25★
- No reported statistical tests were found to recompute.
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run on this paper: the pass that reads its reported means did not complete. No reported mean was checked for arithmetic impossibility.
- 01Data and code not shared
Data availability statement is vague (on request without a mechanism), and no analysis code is shared.
“No computer code was used for data collection.”
MethodsFind in source
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
The paper is a well-conducted and clearly reported phase 2 trial with strong scientific premise, adequate randomization, detailed eligibility criteria, and transparent reporting of ethics, demographics, and limitations. The main weaknesses are reproducibility-related: a vague data-availability statement with no managed-access mechanism, no shared analysis code, threshold-only p-values, and missing manufacturer/source information for the investigational products.
All three independent reviewer runs were synthesized at the checklist level; the main divergences (study design pass vs warn; statistical analysis pass vs warn; data code availability fail vs warn) were resolved by weighing the specific evidence and the scoring rules. The statistics verification component recomputed 0 tests (none met the machine-verifiable criteria), so statistical correctness beyond the reported consistency is unverified. No retracted or non-findable references were flagged; the one reproducibility link checked was live.
Numerical inconsistencies
None foundValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
Checked — nothing surfaced.
Overstated conclusions
None found · partly checkedConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
Nothing surfaced — but not everything feeding this category ran (missing: surrogate-endpoint assessment), so read this as a partial clean bill.
9 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 3Elebsiran plus PEG-IFNα improved HBsAg loss rates compared with PEG-IFNα alone.The paper provides direct evidence from the randomized part I, showing higher HBsAg loss rates in cohorts 2 and 3 vs cohort 1 at both EOT and 24 weeks post-EOT (Table 2).Evidence: Table 2 shows HBsAg loss at 24 weeks post-EOT: 5.6% (cohort 1) vs 21.1% and 33.3% (cohorts 2 and 3).
“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.”
Table 2Find in source - supportedReviewer 1Prior response to the BRII-179 vaccine was associated with higher HBsAg clearance, suggesting its potential as a predictive tool.The paper shows that in cohort 4, BRII-179 anti-HBs responders had higher HBsAg loss rates at 24 weeks post-EOT (42.1%) compared with nonresponders (8.3%).Evidence: Table 3 shows HBsAg loss at 24 weeks post-EOT: 42.1% (responders) vs 8.3% (nonresponders).
“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%).”
Table 3Find in source - supportedReviewers 1, 2, 3Elebsiran and PEG-IFNα combination therapy was generally safe and well tolerated.Safety data show most TEAEs were grade 1-2, no deaths, and few SAEs. The safety profile is consistent with PEG-IFNα.Evidence: Table 4 and safety results show no deaths, low discontinuation rates, and no new safety signals.
“Most TEAEs were consistent with established adverse reactions of PEG-IFNα.”
AbstractFind in source - supportedReviewers 1, 3The 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.The subgroup analysis supports the claim, and the paper appropriately caveats it as a suggestion requiring further study.Evidence: Table 3 shows higher HBsAg loss in responders; Discussion notes need for larger studies.
“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.”
DiscussionFind in source - supportedReviewers 2, 3These results demonstrate an additive benefit of elebsiran when combined with PEG-IFNα in achieving sustained HBsAg loss.The randomized comparison (cohorts 1-3) shows higher HBsAg loss rates in combination arms (21.1%, 33.3%) vs monotherapy (5.6%) at 24 weeks post-EOT, supporting an additive benefit.Evidence: Table 2: HBsAg loss at 24 weeks post-EOT: cohort 1: 5.6%, cohort 2: 21.1%, cohort 3: 33.3%.
“These results demonstrate an additive benefit of elebsiran when combined with PEG-IFNα in achieving sustained HBsAg loss.”
AbstractFind in source - supportedReviewer 2Furthermore, 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 cohort 4, BRII-179 anti-HBs responders had higher HBsAg loss (42.1%) than nonresponders (8.3%) at 24 weeks post-EOT, supporting the claim.Evidence: Table 3: HBsAg loss at 24 weeks post-EOT: responders 42.1%, nonresponders 8.3%.
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.
Abstractreviewer’s wording - supportedReviewer 2Elebsiran plus PEG-IFNα improved hepatitis B surface antigen (HBsAg) loss rates compared with PEG-IFNα alone in patients with chronic hepatitis B virus infection.Same as above; the randomized data directly support this claim.Evidence: Table 2, as above.
“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.”
AbstractFind in source - supportedReviewer 2Furthermore, 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.Cohort 4 data show a clear association: responders had higher HBsAg loss. The claim is supported.Evidence: Table 3, as above.
“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.”
AbstractFind in source - supportedReviewer 3Prior response to BRII-179 vaccine was associated with higher HBsAg clearance, suggesting its potential as a predictive tool.Cohort 4 data show higher HBsAg loss in anti-HBs responders (42.1%) vs nonresponders (8.3%) at 24 weeks post-EOT, supporting the claim.Evidence: Table 3: HBsAg loss at 24 weeks post-EOT in cohort 4 subgroups: responders 8/19 (42.1%), nonresponders 1/12 (8.3%).
HBsAg loss occurred in 8 of 19 BRII-179 anti-HBs responders (42.1%) compared with 1 of 12 nonresponders (8.3%).
Resultsreviewer’s wording
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
2 findings · worst highRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data and code not sharedAssessed
- Key resources under-identified (antibodies, cell lines, RRIDs)Assessed
The paper cites prior studies on elebsiran, PEG-IFNα, and BRII-179, acknowledges the lack of a PEG-IFNα control in earlier work, and provides a logical rationale for the combination therapy and the use of BRII-179 for immunological profiling. Limitations of the current study and prior work are discussed.
“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”
The randomized part I uses a validated computerized system for randomization, stratified by HBsAg levels. Participants are the unit of randomization. The open-label nature is stated in the title and methods but no rationale for lack of blinding is provided. A Bayesian sample size calculation is presented. Detailed inclusion/exclusion criteria are given. Analysis sets (mITT, modified efficacy, safety) are pre-specified. The PEG-IFNα monotherapy arm serves as an active control.
“The randomization code was generated through a validated computerized system.”
“open-label, phase 2 trial”
“The actual sample size was informed by a Bayesian statistical model. Specifically, with 15 participants per cohort, the lower bounds of the 95% CrI would exclude a response rate of 10%, provided the observed response rate was greater than 27%.”
“The randomization code was generated through a validated computerized system.”
“Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial”
“The actual sample size was informed by a Bayesian statistical model. Specifically, with 15 participants per cohort, the lower bounds of the 95% CrI would exclude a response rate of 10%, provided the observed response rate was greater than 27%.”
“open-label, phase 2 study”
Table 1 provides sex, age, BMI, race, HBsAg levels, anti-HBs, ALT, HBeAg status for all cohorts. The study enrolls both sexes (mostly male) and reports demographics adequately.
“Table 1 Demographics and baseline characteristics”
“ALT and AST ≤ ULN”
The study was approved by an independent ethics committee or institutional review board at each site (list provided in supplement), conducted in accordance with the Declaration of Helsinki and ICH-GCP, and all participants provided written informed consent.
“All participants provided written informed consent to participate in the study before any study-specific procedures were conducted.”
“conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice.”
“All participants provided written informed consent to participate in the study before any study-specific procedures were conducted.”
“conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice.”
Reagents_identified is scored against the investigational products. Elebsiran and PEG-IFNα are named with doses, but no manufacturer, catalog number, or lot number is provided. Software (SAS version 9.4) is adequately identified. All other resource categories are not applicable.
“PEG-IFNα 180 μg administered subcutaneously (SC) every week”
“SAS version 9.4 was used for data analyses in this study.”
“SAS version 9.4 was used for data analyses in this study.”
“SAS version 9.4 was used for data analyses in this study.”
The primary analysis uses Bayesian estimation with credible intervals, which is acceptable. The mixed model for repeated measures is named. Assumptions are handled by design. Effect sizes are reported with CIs. Data presentation includes per-group n and error bars. The only shortcoming is that the reported p-value is imprecise ('P < 0.05').
“Point estimate of response, % (95% CrI)”
“P < 0.05; Extended Data Table”
“Point estimate of response, % (95% CrI) | 5.4 (0.1, 18.1) | 26.2 (10.3, 45.4) | 33.3 (17.1, 49.5)”
The data availability statement says deidentified individual participant data will be shared on request or after trial completion, but does not name a managed-access platform or data-access committee. The study protocol and SAP are available. No code was shared; the paper states no computer code was used for data collection, but analysis code (SAS) is not mentioned.
“No computer code was used for data collection.”
“No computer code was used for data collection.”
The methods are sufficiently detailed for replication. The trial is registered (NCT05970289). CONSORT adherence is stated. All primary and secondary outcomes are reported. Limitations are discussed in the Discussion. Conclusions are proportional to the evidence. Funding and competing interests are declared.
“ClinicalTrials.gov registration: NCT05970289”
“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”
“Secondary objectives were to assess the antiviral activity of elebsiran and PEG-IFNα combination therapy, and to assess elebsiran pharmacokinetics exposure (endpoint: plasma concentrations of elebsiran and its metabolite at selected time points) and evaluate antidrug antibody to elebsiran (endpoint: the occurrence of antidrug antibody to elebsiran and associated titer, if positive).”
“ClinicalTrials.gov registration: NCT05970289”
“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”
“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”
“ClinicalTrials.gov registration: NCT05970289”
“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”
“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 24 references by DOI: 19 verified — 5 no DOI (shown, not verified).
- NO DOIGuidelines for the Prevention, Diagnosis, Care and Treatment for People with Chronic Hepatitis B InfectionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGlobal Hepatitis Report 2024: Action for Access in Low- and Middle-Income CountriesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIHepatitis B Vaccine (Recombinant) (PREHEVBRIO®) [Package Insert]No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIEfficacy and safety of elebsiran and pegylated interferon alfa combination therapy versus pegylated interferon alfa in participants with chronic hepatitis B virus infection: follow-up results from ongoing phase 2, randomized, open-label ENSURE studyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIChronic hepatitis B virus infected participants responding to prior BRII-179 treatment achieved faster and higher rate of hepatitis B virus surface antigen seroclearance on elebsiran plus peginterferon-alfa: end of treatment data from ENSURE studyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://clinicaltrials.gov/study/NCT05970289?term=NCT05970289&rank=1LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
4 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 4 minor suggestions below.
4 copyedit issues flagged: mostly consistency, clarity, punctuation.
- MINORconsistencyMethods, 'Study design' paragraph“see ‘Ethics committees/institutional review boards that approved the study protocol’ in the”→ Add a complete reference to the supplementary file, e.g., 'see Supplementary Information'.Placeholder text appears incomplete.
- MINORconsistencyMain text, paragraph 2“PEG-IFNα”→ Ensure consistent use of hyphenation (PEG-IFNα vs PEG-IFNα) throughout; the paper uses both.The paper uses 'PEG-IFNα' consistently, but check for any instances of 'PEG-IFNα' without hyphen.
- MINORclarityMethods, Statistical methods“The actual sample size was informed by a Bayesian statistical model.”→ Consider clarifying that the sample size was determined by a Bayesian approach rather than a frequentist power analysis, to avoid confusion.The sentence is clear but could be expanded for readers unfamiliar with Bayesian sample size determination.
- MINORpunctuationReferences, line 24“itis B virus infection: follow-up results from ongoing phase 2, randomized, open-label ENSURE study. LBP-016. J. Hepatol. 82 , S77 (2025).”→ Correct the truncated reference title: 'Hepatitis B virus infection...'The reference appears to be cut off; it should start with 'Hepatitis'.
Post-publication: the published work is methodologically sound and its core clinical findings can be read with reasonable confidence, but the vague data-sharing statement and absence of analysis code materially weaken reproducibility, and the threshold p-values obscure effect-size precision. An informed reader should weigh the open-label design without justification and the unreported secondary PK/antidrug-antibody endpoints. These issues would warrant a correction or data-supplement update (data-sharing mechanism, exact p-values, product sourcing) rather than a retraction or re-analysis.
- 1.HIGHdata codeReplace the vague 'on request' data availability statement in the Data availability section with a named managed-access platform (e.g., Vivli, YODA) or a data-access committee with explicit conditions and timeline.The current statement provides no concrete mechanism for accessing deidentified IPD, undermining the reproducibility of the published results.
- 2.HIGHdata codeDeposit the SAS analysis code in a public repository (e.g., Zenodo, GitHub) with a DOI and cite it in the Methods or Data availability section.Sharing the analysis code enables independent verification of the reported Bayesian and mixed-model analyses.
- 3.HIGHstatisticsReport exact p-values (e.g., 'P = 0.023') instead of 'P < 0.05' for the mixed-model comparisons in the main text and Extended Data tables.Threshold-only p-values obscure the strength of evidence and are a recognized reporting deficiency.
- 4.HIGHotherAdd the manufacturer/source (and lot numbers if available) for elebsiran, PEG-IFNα, and BRII-179 in the Methods.Reagents identification is currently inadequate, hindering replication and proper attribution.
- 5.MEDIUMotherAdd a brief rationale for the open-label design in the Methods (e.g., feasibility of blinding subcutaneous injections).The absence of a justification for the lack of blinding is a reporting gap in an interventional trial.
- 6.MEDIUMstatisticsDescribe the handling of missing data and outliers (e.g., imputation methods, sensitivity analyses) in the statistical methods.Outlier and missing-data approaches are not pre-specified, which is a reproducibility gap.
- 7.MEDIUMreportingReport the pre-specified secondary endpoints of elebsiran pharmacokinetics and antidrug antibodies, or explicitly state where they will be reported.Not all pre-specified secondary outcomes appear in this paper, which is a transparency concern.
- 8.MEDIUMcopyeditCorrect the truncated reference title in the References (line 24) so it begins 'Hepatitis B virus infection...'.The reference appears cut off, which is an integrity/consistency error in the citation list.
- 9.LOWcopyeditComplete the pointer to the supplementary file for the ethics committee approval list (e.g., 'see Supplementary Information').The current placeholder text appears incomplete.
- 10.LOWcopyeditEnsure consistent hyphenation of 'PEG-IFNα' throughout the manuscript.Minor terminology consistency issue flagged by the copyedit pass.
- 11.LOWcopyeditClarify in the statistical methods that the sample size was determined by a Bayesian approach rather than a frequentist power analysis.Reduces reader confusion about the absence of a conventional power calculation.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
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