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
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-22
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/3138f0e3-8780-4228-a596-271d173f5d64 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- ReportingStudy design partially met−0.25★
- ReportingData & code availability partially met−0.25★
- No reported statistical tests were found to recompute.
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 5 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy endpoint is HBsAg loss, which is a surrogate marker for functional cure in chronic hepatitis B. The paper does not demonstrate that HBsAg loss at 24 weeks post-treatment translates into hard clinical outcomes such as reduced mortality, cirrhosis, or hepatocellular carcinoma. Although HBsAg loss is a recognized goal, the manuscript does not cite validated evidence linking this surrogate to long-term clinical benefit in the context of this trial, nor does it show target engagement at the tested dose beyond HBsAg reduction.
“Primary endpoints were HBsAg loss at the end of treatment (EOT) and 24 weeks post-EOT.”
- 02Treatment effect not shown to be clinically meaningful
The reported effect sizes are small absolute percentages (e.g., 21.1%, 33.3% vs 5.6% in part I; 29.0% overall in part II) and are not anchored to a minimal clinically important difference or to long-term clinical outcomes. The manuscript does not provide a threshold for clinical meaningfulness of HBsAg loss rates, and the small sample sizes and Bayesian credible intervals suggest uncertainty.
“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…”
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 phase 2 trial with a clear scientific premise, appropriate statistical methods, and transparent reporting. The main weaknesses are the lack of justification for the open-label design, absence of a formal power analysis for the single-arm cohort, and a vague data availability statement.
Both reviewers classified the study as interventional, which is adopted. The evaluation covers all eight rigor dimensions; no dimensions were excluded as not applicable. The reviewers agreed on all dimensions except study design (one pass, one warn), where the synthesized judgment is 'warn' based on the preponderance of evidence.
Numerical inconsistencies
1 finding · worst lowValues 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.
- Internal contradictions in the reported numbersAssessed
- lowinternal contradictionIn Table 4, cohort 3 has 5 participants with grade 3 TEAEs (27.8%) but the text states 6 of 18 (33.3%) for grade ≥3 TEAEs. This may be due to grade 4 events, but the table shows grade 3 and grade 4 separately, and the text says 'Grade ≥3 TEAEs were reported in ... 6 of 18 participants (33.3%) in cohort 3'. The table shows grade 3: 5 (27.8%) and grade 4: 1 (5.6%), which sum to 6 (33.3%). This is consistent.
Grade ≥3 TEAEs were reported in 6 of 18 participants (33.3%) in cohort 3
Resultsreviewer’s wording - lowinternal contradictionThe abstract reports HBsAg loss at 24 weeks post-EOT for cohort 2 as 4 out of 19 (21.1%), but the text in Results states '4 of 19 participants (21.1%) in cohort 2' which is consistent. No contradiction found.
“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”
AbstractFind in source
Overstated conclusions
3 findings · worst highConclusions 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.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
4 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2BRII-179 may be a valuable tool for immunological profiling to optimize curative outcomes.The association is suggestive but based on a small, non-randomized cohort; the claim is appropriately cautious.Evidence: Cohort 4 subgroup analysis shows higher HBsAg loss in responders.
“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.”
AbstractFind in source - supportedReviewers 1, 2Elebsiran plus PEG-IFNα improved HBsAg loss rates compared with PEG-IFNα alone.The randomized comparison shows higher HBsAg loss rates in combination arms versus monotherapy.Evidence: Table 2: HBsAg loss at 24 weeks post-EOT: 21.1% (cohort 2) and 33.3% (cohort 3) vs 5.6% (cohort 1).
“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 - supportedReviewers 1, 2Prior response to BRII-179 vaccine was associated with higher HBsAg clearance.In cohort 4, responders had higher HBsAg loss rates than nonresponders.Evidence: Table 3: 42.1% vs 8.3% at 24 weeks post-EOT.
“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 - supportedReviewers 1, 2Elebsiran and PEG-IFNα combination therapy was generally safe and well tolerated.Safety data show comparable TEAE rates across cohorts, with no deaths and few SAEs.Evidence: Table 4: SAEs 11.1%, 5.3%, 0%, 3.2% across cohorts; no deaths.
“Elebsiran and PEG-IFNα combination therapy was generally safe and well tolerated.”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy endpoint is HBsAg loss, which is a surrogate marker for functional cure in chronic hepatitis B. The paper does not demonstrate that HBsAg loss at 24 weeks post-treatment translates into hard clinical outcomes such as reduced mortality, cirrhosis, or hepatocellular carcinoma. Although HBsAg loss is a recognized goal, the manuscript does not cite validated evidence linking this surrogate to long-term clinical benefit in the context of this trial, nor does it show target engagement at the tested dose beyond HBsAg reduction.
“Primary endpoints were HBsAg loss at the end of treatment (EOT) and 24 weeks post-EOT.”
- INADEQUATEEffect sizeThe reported effect sizes are small absolute percentages (e.g., 21.1%, 33.3% vs 5.6% in part I; 29.0% overall in part II) and are not anchored to a minimal clinically important difference or to long-term clinical outcomes. The manuscript does not provide a threshold for clinical meaningfulness of HBsAg loss rates, and the small sample sizes and Bayesian credible intervals suggest uncertainty.
“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.”
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 mediumRequired 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/code availability incompleteAssessed
- Study-design details incomplete (controls, blinding, power)Assessed
The introduction cites prior studies on elebsiran and PEG-IFNα, acknowledges the lack of a monotherapy control in a prior study, and hypothesizes that BRII-179 responders may benefit more. Limitations of prior research are addressed by including a PEG-IFNα monotherapy control in part I.
“It was hypothesized that individuals with chronic HBV infection who were able to overcome HBV-induced immune dysfunction following exposure to BRII-179 may have an increased likelihood of mounting an effective immune response upon subsequent treatment with elebsiran and PEG-IFNα, potentially leading to higher rates of functional cure.”
“However, this study lacked a PEG-IFNα monotherapy control, limiting direct comparison.”
“It was hypothesized that individuals with chronic HBV infection who were able to overcome HBV-induced immune dysfunction following exposure to BRII-179 may have an increased likelihood of mounting an effective immune response upon subsequent treatment with elebsiran and PEG-IFNα, potentially leading to higher rates of functional cure.”
Randomization method (Interactive Response Technology) and stratification are reported. Blinding is absent (open-label) but stated. Power analysis is reported for part I but not for cohort 4. Inclusion/exclusion criteria are detailed. Outlier handling is not explicitly described. Controls are present (PEG-IFNα monotherapy). Independent replication is not reported.
“using an Interactive Response Technology system. The randomization code was generated through a validated computerized system. Participants were stratified at randomization by their HBsAg level at screening (>100 to ≤500 IU ml −1 , >500 to ≤1,500 IU ml −1 and >1,500 to ≤3,000 IU ml −1 ).”
“partially randomized, open-label, phase 2 trial”
“using an Interactive Response Technology system. The randomization code was generated through a validated computerized system.”
“This ongoing, open-label, phase 2 study”
“The actual sample size was informed by a Bayesian statistical model.”
Sex, age, race, BMI, HBsAg, HBeAg, and ALT are reported in Table 1. Both sexes are enrolled, so sex justification is not applicable. Demographics are comprehensive.
“Male | 16 (88.9) | 17 (89.5) | 14 (77.8) | 47 (85.5) | 23 (74.2)”
“Baseline HBsAg levels ranged from 2.02 to 3.39 log 10 (IU ml −1 ), with a mean (s.d.) of 2.78 (0.37) log 10 (IU ml −1 ).”
The study was approved by an independent ethics committee or IRB at each site, all participants provided written informed consent, and the study was conducted in accordance with the Declaration of Helsinki and ICH-GCP.
“The study was approved by an independent ethics committee or institutional review board at each site”
“All participants provided written informed consent to participate in the study before any study-specific procedures were conducted.”
“and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice.”
Elebsiran and PEG-IFNα are named with doses and regimens. Assays (Cobas, Roche) are identified with LLOQs. No antibodies, cell lines, or mycoplasma testing are applicable.
“Virology assessments included quantitative measurement of serum HBsAg (Cobas, ELECSYS HBsAg II quant II (Roche); LLOQ: 0.05 IU ml −1 )”
“SAS version 9.4 was used for data analyses in this study.”
“cohort 2 (48 doses of PEG-IFNα 180 μg administered SC QW and 13 doses of elebsiran 200 mg administered SC every 4 weeks (Q4W)”
“quantitative measurement of serum HBsAg (Cobas, ELECSYS HBsAg II quant II (Roche); LLOQ: 0.05 IU ml −1 )”
“SAS version 9.4 was used for data analyses in this study.”
Tests are named (Bayesian hierarchical model, mixed model for repeated measures). Assumptions are handled by design. Exact p-values are not reported; instead, credible intervals are used, which is acceptable. Effect sizes are reported with CIs. Software is identified. Data presentation includes individual data points and error bars. Mathematical plausibility checks were not possible due to continuous data and small N.
“For the primary efficacy endpoints, an estimation approach with no hypothesis testing was used for analysis. A Bayesian hierarchical model was used as the primary analysis to estimate the posterior probability of the response rate for each of cohorts 1–3”
“Point estimate of response, % (95% CrI) | 5.4 (0.1, 18.1) | 26.2 (10.3, 45.4) | 33.3 (17.1, 49.5)”
“For the primary efficacy endpoints, an estimation approach with no hypothesis testing was used for analysis.”
“Point estimate of response, % (95% CrI) | 5.4 (0.1, 18.1) | 26.2 (10.3, 45.4) | 33.3 (17.1, 49.5)”
“For cohorts 1–3, changes from baseline in HBsAg (on a log 10 scale) at all scheduled visits were statistically analyzed using a mixed model for repeated measures.”
The data availability statement says deidentified individual participant data will be shared on request or after trial completion, but no platform or timeframe is specified. No code is shared. Since this is a clinical trial, repository deposit is not applicable for patient data.
“Owing to the ongoing nature of the ENSURE study, the deidentified individual participant data that underlie the results reported in this Article will be shared on request, or after the completion of the trial within the timeframe as required by ClinicalTrial.gov”
“Owing to the ongoing nature of the ENSURE study, the deidentified individual participant data that underlie the results reported in this Article will be shared on request, or after the completion of the trial within the timeframe as required by ClinicalTrial.gov”
The trial is registered (NCT05970289). CONSORT guidelines are followed. All outcomes are reported. Limitations are discussed. Conclusions are proportional. Funding and COI are disclosed.
“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.”
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
6 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 6 minor suggestions below.
6 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORconsistencyAbstract“partially randomized, open-label, phase 2 trial”→ Consider clarifying that part II is single-arm, not randomized.The abstract describes the study as partially randomized, which is accurate but could be clearer.
- MINORtypoDiscussion“immunological markersare associated”→ Add a space: 'markers are'Missing space in 'markersare'.
- MINORclarityMethods, Statistical methods“The post probability of true response rate >0.15 is more than 90%.”→ Clarify as 'The posterior probability that the true response rate is >0.15 is more than 90%.'The phrase 'post probability' is unclear; likely means 'posterior probability'.
- MINORtypoDiscussion, paragraph 7“immune markersare”→ immune markers areMissing space between 'markers' and 'are'.
- MINORconsistencyTable 1“>500- to ≤1,500”→ >500 to ≤1,500Inconsistent use of hyphen in range.
- MINORclarityData availability“For inquiries, the contact person is Z.H. are provided with this paper.”→ For inquiries, the contact person is Z.H.Grammatically incomplete sentence.
As a post-publication audit, the published work is methodologically sound but has reporting gaps that an informed reader should weigh: the open-label design is not justified, the single-arm cohort lacks a formal sample size calculation, and the data availability statement is vague. These issues do not invalidate the findings but warrant caution in interpretation and could be addressed via a correction or data-sharing clarification.
- 1.HIGHreportingIn the Methods (Study design), add a rationale for the open-label design, explaining why blinding was not feasible or why it was not used.The absence of blinding is a potential source of bias; justifying it helps readers assess the risk.
- 2.HIGHreportingIn the Methods (Statistical methods), provide a formal sample size calculation or power analysis for cohort 4, even if exploratory, specifying the effect size, alpha, and power.Without a sample size justification, the precision of estimates from the single-arm cohort is unclear.
- 3.HIGHdata codeIn the Data availability section, specify a concrete data access mechanism (e.g., a named data access committee or platform like Vivli) with conditions and a timeframe for sharing.The current vague statement ('on request') does not meet journal standards for data availability and limits reproducibility.
- 4.MEDIUMreportingIn the Methods (Statistical methods), clarify how outliers and missing data were handled in the analysis.Outlier and missing data handling are essential for reproducibility and are currently not reported.
- 5.MEDIUMreportingIn the Discussion, add a statement acknowledging the potential bias introduced by the open-label design as a limitation.Acknowledging this limitation strengthens the transparency of the manuscript.
- 6.MEDIUMdata codeAdd a code availability statement in the Data availability section, even if the SAS code is available on request.Sharing analysis code enhances reproducibility, even if it is not deposited in a public repository.
- 7.MEDIUMreportingIn the Methods (Statistical methods), provide more detail on the Bayesian model priors and any sensitivity analyses performed.Specifying priors and sensitivity analyses improves the reproducibility of the Bayesian analysis.
- 8.MEDIUMreportingIn the Methods, specify the version of the CONSORT checklist used and how it was followed.Explicitly stating the CONSORT version and adherence details strengthens reporting transparency.
- 9.LOWcopyeditIn the Discussion, fix the missing space in 'immunological markersare associated' to 'immunological markers are associated'.Typographical errors reduce readability and professionalism.
- 10.LOWcopyeditIn the Methods (Statistical methods), clarify 'post probability' to 'posterior probability'.The term 'post probability' is non-standard and may confuse readers.
- 11.LOWcopyeditIn Table 1, standardize the range notation from '>500- to ≤1,500' to '>500 to ≤1,500'.Consistent formatting improves clarity.
- 12.LOWcopyeditIn the Data availability section, correct the grammatically incomplete sentence: 'For inquiries, the contact person is Z.H. are provided with this paper.' to 'For inquiries, the contact person is Z.H.'Grammatical errors detract from the manuscript's quality.
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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