A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial.
Diacon AH, Barry CE 3rd, Carlton A, Chen RY, Davies M, de Jager V, Fletcher K, Koh GCKW, Kontsevaya I, Heyckendorf J, Lange C, Reimann M, Penman SL, Scott R, Maher-Edwards G, Tiberi S, Vlasakakis G, Upton CM, Aguirre DB
- DOI
- 10.1038/s41591-024-02829-7
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-21
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/bbbb94fc-348a-4292-ada4-b5135587eddd is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- 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★
- CitationsUnresolved reference−0.25★
- Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy endpoint is early bactericidal activity (EBA), measured as the rate of change in log10 CFU/ml sputum and time to sputum culture positivity (TTP). These are microbiological surrogate markers for clinical outcome (cure, relapse, mortality). The paper does not provide evidence linking EBA to long-term clinical outcomes, nor does it demonstrate target engagement at the tested doses beyond PK/PD modeling. The claim of 'bactericidal activity' is based on these surrogate endpoints.
“Assessing the EBA (the measure of efficacy used in this study) of anti-TB drugs by determining the viable sputum load of M. tuberculosis over the first 14 days of treatment is an established method for the early clinical evaluation of new agents”
- 02Treatment effect not shown to be clinically meaningful
The reported effect sizes are numerical reductions in log10 CFU/ml sputum, but the magnitude is not anchored to a clinically meaningful threshold. The paper does not state a minimal clinically important difference for EBA, and the reductions are described as 'numerical' without statistical significance testing. The effect size is not presented as a fraction of normal or compared to a reference value.
“We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole.”
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 2a dose-ranging trial with clear scientific premise, adequate ethics, and transparent reporting. The main weaknesses are the absence of a formal power analysis, partial blinding, and lack of explicit outlier handling, which are typical for exploratory phase 2a studies but should be acknowledged.
Both reviewers classified the study as interventional; no divergence. The statistics component recomputed 0 tests (coverage limited to tests with test statistic+df or effect+CI), so no statistical claims are independently verified. The citation check found 1 reference not found in registry (potential fabrication signal).
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 contradictionThe abstract states '75 males were treated' but the results section reports 76 enrolled and randomized. The discrepancy may be due to one participant not receiving treatment, but this is not explicitly clarified.
Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care ... Of the 168 male participants ... 76 (45%) were enrolled and randomized
Abstractreviewer’s wording
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
8 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, 2Ganfeborole is a potential candidate for combination treatment of tuberculosis.The demonstrated EBA and safety support this claim, but the study is a short monotherapy trial; combination efficacy is not directly tested.Evidence: The discussion extrapolates from the EBA results to potential combination use.
“The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.”
DiscussionFind in source - supportedReviewer 1Ganfeborole demonstrates early bactericidal activity in participants with tuberculosis.The paper reports numerical reductions in CFU and increases in TTP for the 5-30 mg doses, which are the primary efficacy endpoints.Evidence: Figure 2 shows decreases in log10 CFU and increases in TTP for ganfeborole 5-30 mg and SOC.
“Participants receiving ganfeborole 5–30 mg and SOC displayed a decrease in log 10 CFU/ml sputum (Fig. ) and an increase in TTP (Fig. ) over time, indicating positive responses for both endpoints.”
ResultsFind in source - supportedReviewer 1Ganfeborole is safe and well tolerated.The paper reports that all AEs were grade 1 or 2, no SAEs occurred, and AE rates were comparable across groups.Evidence: Table 2 shows no SAEs and mostly grade 1/2 AEs.
“All AEs reported during this study were either grade 1 or grade 2. No serious AEs (SAEs) were reported.”
ResultsFind in source - supportedReviewer 1Ganfeborole 30 mg shows measurable treatment responses on PET/CT scans.The post hoc exploratory analysis shows reductions in lesion radiodensity and total glycolytic activity in most participants receiving 30 mg.Evidence: Figure 3 shows changes in TGA and TAM for 30 mg participants.
Treatment with ganfeborole 30 mg was associated with a reduction in lesion-associated radiodensity across aggregated matched cubes in all participants and to a reduction in lesion total glycolytic activity in 11/13 participants.
Resultsreviewer’s wording - supportedReviewer 2Ganfeborole demonstrates bactericidal activity in participants with tuberculosis.The claim is supported by the observed reductions in log10 CFU and increases in TTP in the 5-30 mg groups.Evidence: Figure 2 shows decreases in log10 CFU and increases in TTP for ganfeborole 5-30 mg and SOC.
“We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole.”
AbstractFind in source - supportedReviewer 2Ganfeborole has an acceptable safety profile.The claim is supported by the reported adverse events being grade 1 or 2 and no serious adverse events.Evidence: Table 2 shows all AEs were grade 1 or 2, and no SAEs were reported.
“Adverse event rates were comparable across groups; all events were grade 1 or 2.”
AbstractFind in source - supportedReviewer 2PET/CT findings show measurable treatment responses in participants receiving ganfeborole 30 mg.The claim is supported by the post hoc exploratory analysis showing reductions in lesion radiodensity and total glycolytic activity in most participants.Evidence: Figure 3 shows reductions in TGA and TAM for 30 mg group.
“In a participant subset, post hoc exploratory computational analysis of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14.”
AbstractFind in source - supportedReviewer 2Whole-blood transcriptional analysis reveals a strong association with neutrophil-dominated modules.The claim is supported by the gene set enrichment analysis showing neutrophil-related pathways.Evidence: Transcriptional profiling showed differences in neutrophil degranulation and activation with 30 mg.
“Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules.”
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 early bactericidal activity (EBA), measured as the rate of change in log10 CFU/ml sputum and time to sputum culture positivity (TTP). These are microbiological surrogate markers for clinical outcome (cure, relapse, mortality). The paper does not provide evidence linking EBA to long-term clinical outcomes, nor does it demonstrate target engagement at the tested doses beyond PK/PD modeling. The claim of 'bactericidal activity' is based on these surrogate endpoints.
“Assessing the EBA (the measure of efficacy used in this study) of anti-TB drugs by determining the viable sputum load of M. tuberculosis over the first 14 days of treatment is an established method for the early clinical evaluation of new agents”
- INADEQUATEEffect sizeThe reported effect sizes are numerical reductions in log10 CFU/ml sputum, but the magnitude is not anchored to a clinically meaningful threshold. The paper does not state a minimal clinically important difference for EBA, and the reductions are described as 'numerical' without statistical significance testing. The effect size is not presented as a fraction of normal or compared to a reference value.
“We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole.”
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
1 finding · 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.
- Study-design details incomplete (controls, blinding, power)Assessed
The introduction cites prior in vitro, animal, and phase 1 studies of ganfeborole, and explains the need for new TB treatments. The rationale linking the drug's mechanism to the study objectives is clear. Limitations of prior work are implicitly addressed through the study design and discussion.
“In this article, a phase 2a randomized study, the aim was to assess the EBA, safety, and PK of ganfeborole monotherapy at a range of dosages in male participants with a new episode of untreated, rifampicin-susceptible pulmonary TB.”
“New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents.”
Randomization method (permuted blocks) and unit (participant) are reported. Blinding is partial: open-label for participants and investigators, but laboratory staff blinded. A formal power analysis is absent, though simulations are described. Inclusion/exclusion criteria are detailed. Outlier handling is not explicitly described. The SOC group serves as a control. Independent replication is not applicable for a single trial.
“Within each cohort, participants were randomized 3:1 to receive ganfeborole or SOC for drug-susceptible TB using permutated blocks.”
“The study was open label, so neither the participants nor the primary investigators were blinded. However, all laboratory staff involved in analyzing and reporting the log 10 CFU counts and TTP endpoints results were blinded to treatment allocation.”
“As no formal statistical hypothesis was tested, no formal sample size calculation was performed.”
“Within each cohort, participants were randomized 3:1 to receive ganfeborole or SOC for drug-susceptible TB using permutated blocks.”
“However, all laboratory staff involved in analyzing and reporting the log 10 CFU counts and TTP endpoints results were blinded to treatment allocation.”
Sex (all male) is reported and justified by teratogenicity data. Age, weight, BMI, and health status (HIV status) are reported. Demographics (race, smoking) are reported. Species/strain and housing are not applicable for a human trial.
“All participants were male due to preclinical teratogenicity data from animal models that became available after the phase 1 study.”
“All participants were Black, and most smoked <20 cigarettes per day.”
“All participants were male due to preclinical teratogenicity data from animal models that became available after the phase 1 study.”
“Age (years), mean (s.d.) | 37.0 (10.20) | 37.8 (8.38) | 38.1 (10.33) | 39.8 (12.33) | 38.5 (9.82)”
“All participants were Black, and most smoked <20 cigarettes per day.”
The study was approved by a named ethics committee (Pharma-Ethics, South Africa) and regulatory authority. Written informed consent was obtained. Compliance with the Declaration of Helsinki and GCP is stated.
“Ethical approval was granted by Pharma-Ethics, South Africa.”
“All participants provided written informed consent before the performance of any study-specific procedures.”
“Ethical approval was granted by Pharma-Ethics, South Africa.”
“All participants provided written informed consent before the performance of any study-specific procedures.”
“The study was conducted in accordance with ethical principles that have their origins in the Declaration of Helsinki and the principles of good clinical practice.”
The investigational product (ganfeborole) is named with doses and regimen. SOC (Rifafour e-275) is named. Software tools (MIM Maestro, CIBERSORT) are identified with versions. Antibodies, cell lines, and mycoplasma testing are not applicable.
“For the manual analysis, which was carried out by an appropriately trained reader, regions of interest spanning the entire left or right lung were defined in MIM Maestro (6.7.12).”
“For the manual analysis, which was carried out by an appropriately trained reader, regions of interest spanning the entire left or right lung were defined in MIM Maestro (6.7.12).”
“This formed the basis for the application of the CIBERSORT algorithm ( https://cibersortx.stanford.edu/ ).”
Statistical tests are named (mixed model repeated measures, Bayesian regression). Assumptions are handled by design. Exact p-values are not reported; the study uses estimation with CIs. Effect sizes with CIs are reported. Software is identified. Data presentation includes per-group n and CIs. Mathematical plausibility checks were not possible for most data due to continuous outcomes and model-based estimates.
“The primary and secondary efficacy analyses were performed using a mixed model repeated measures analysis.”
“Data are mean estimate (95% CI).”
“The primary and secondary efficacy analyses were performed using a mixed model repeated measures analysis.”
“Data are mean estimate (95% CI).”
“Safety data were summarized descriptively according to the Medical Dictionary for Regulatory Activities version 24.1 and GSK’s Integrated Data Standards Library standards.”
The data availability statement describes a managed access process via GSK's data sharing portals, which is appropriate for patient-level data. No raw data repository deposit or accession numbers are applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.
“External researchers can request access to anonymized patient-level clinical trial data and supporting clinical trial documents through either of two multi-sponsor data sharing portals.”
“External researchers can request access to anonymized patient-level clinical trial data and supporting clinical trial documents through either of two multi-sponsor data sharing portals.”
The trial is registered (NCT03557281). A reporting summary is mentioned. All outcomes are reported. Limitations are discussed. Conclusions are proportional. Funding and COI are disclosed.
“ClinicalTrials.gov identifier: NCT03557281”
“This study has several limitations. The study design did not include a negative control as it is unethical to have a no treatment or placebo group of participants with active TB.”
“ClinicalTrials.gov identifier: NCT03557281”
“Further information on research design is available in the linked to this article.”
“This study has several limitations. The study design did not include a negative control as it is unethical to have a no treatment or placebo group of participants with active TB.”
Registered (2 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
1 finding · worst lowReferences 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.
- References not resolvable to a published paperRecomputed
Checked 34 references by DOI: 25 verified — 1 DOI unresolved, 8 no DOI (shown, not verified).
- UNRESOLVED10.1164/arrd.1980.121.6.939The early bactericidal activity of drugs in patients with pulmonary tuberculosisCited DOI does not resolve to any Crossref record.
- NO DOITuberculosis Fact SheetNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIThe END TB StrategyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGlobal Tuberculosis Report 2022No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPhase 2a trial of GSK3036656 in rifampicin-susceptible pulmonary tuberculosis: PET/CT scan resultsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIResearching the prevalence of tuberculosis in marginalized populations: a socioeconomic analysis of Black South Africans and Canadian Indigenous populationsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGSK3036656 Investigator BrochureNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISouth African National Tuberculosis Management Guidelines 2014No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIKEGG PATHWAY databaseNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
4 data/code links checked; 4 live.
- datahttps://clinicaltrials.gov/study/NCT03557281LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT05382312LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://www.gsk-studyregister.com/en/LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- codehttps://cibersortx.stanford.edu/LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly typo, consistency, clarity.
- MINORtypoExtended Data Table 1“langauge”→ languageTypo in 'Plain Language Summary' description.
- MINORconsistencyResults, Participant disposition“76 (45%) were enrolled”→ Verify the number against the CONSORT diagram.Potential inconsistency in enrollment numbers.
- MINORtypoAbstract“18 F-fluorodeoxyglucose”→ Use superscript for 18F: ¹⁸F-fluorodeoxyglucoseFormatting issue.
- MINORconsistencyResults, Participant disposition“100% ( n = 18), 89% ( n = 8), 82% ( n = 14), 88% ( n = 14) and 87% ( n = 13)”→ Ensure the percentages match the n values (e.g., 8/9 = 89%, 14/17 = 82%, 14/16 = 88%, 13/15 = 87%).Percentages are consistent with the n values.
- MINORclarityMethods, Statistical analysis“A bilinear Bayesian regression model was also used for EBA CFU and TTP for baseline to Day 14; this model is recommended for the analysis of EBA endpoints in TB because they can follow a bilinear rate of change.”→ Clarify whether the bilinear model was used for primary or sensitivity analysis.Ambiguity in the role of the bilinear model.
The published work is generally robust, but readers should weigh the lack of formal power analysis and partial blinding when interpreting effect sizes. The unresolved reference and minor internal inconsistencies (e.g., 75 vs 76 participants) warrant attention; an erratum or clarification may be appropriate.
- 1.HIGHreportingIn the Methods, Statistical analysis section, add a statement on how outliers were handled, or explicitly state that no outliers were excluded.Outlier handling is a standard reporting requirement and its absence is a gap that readers may question.
- 2.HIGHreportingIn the Methods, clarify the role of the bilinear Bayesian regression model (primary vs sensitivity analysis) and specify the statistical software (e.g., SAS, R) with version numbers.Ambiguity in the analysis plan and missing software details reduce reproducibility.
- 3.HIGHreportingVerify and correct the reference 'The early bactericidal activity of drugs in patients with pulmonary tuberculosis' (DOI 10.1164/arrd.1980.121.6.939) which was not found in Crossref/OpenAlex; confirm it exists or replace it.An unresolved reference may indicate a fabrication or citation error, which is a serious integrity concern.
- 4.MEDIUMreportingIn the Results, reconcile the discrepancy between the abstract's '75 males were treated' and the results' '76 enrolled and randomized'; clarify whether one participant did not receive treatment.Internal inconsistency in participant numbers could confuse readers and undermine trust.
- 5.MEDIUMreportingIn the Methods, specify the manufacturer/source of ganfeborole and the SOC (Rifafour e-275) to fully identify the investigational products.Complete identification of key resources is essential for reproducibility.
- 6.MEDIUMreportingIn the Methods, provide version numbers for all software used (e.g., custom segmentation software) to enhance reproducibility.Missing software versions hinder replication of the analysis.
- 7.MEDIUMreportingIn the Results, consider reporting exact p-values for key comparisons, even though the study is primarily estimation-based, to facilitate meta-analyses.Exact p-values are useful for future meta-analyses and are expected by some readers.
- 8.MEDIUMreportingIn the Discussion, explicitly address the potential impact of the open-label design on the results, even though laboratory staff were blinded.Acknowledging the limitation of open-label design strengthens the interpretation.
- 9.MEDIUMdata codeIn the Data Availability section, provide a direct link to the data sharing portal or a specific accession number for the dataset.A concrete link or accession number makes the data access route more actionable.
- 10.MEDIUMreportingIn the Methods, state whether any data were imputed for missing sputum samples or other missing data.Handling of missing data is a key methodological detail that is currently absent.
- 11.MEDIUMreportingIn the Results, for the PET/CT exploratory analysis, report the number of participants with each lesion type to clarify the subgroup analyses.Providing subgroup sample sizes improves transparency of exploratory analyses.
- 12.MEDIUMreportingIn the Discussion, clarify that the PET/CT and transcriptional analyses are exploratory and hypothesis-generating, not confirmatory.Explicitly labeling exploratory analyses prevents over-interpretation.
- 13.LOWcopyeditFix typo 'langauge' to 'language' in Extended Data Table 1.Correcting typos improves professionalism.
- 14.LOWcopyeditUse superscript for 18F in '18F-fluorodeoxyglucose' in the Abstract.Proper formatting of isotopes is standard scientific notation.
- 15.LOWcopyeditVerify the enrollment number '76 (45%)' against the CONSORT diagram in the Results.Ensuring consistency between text and CONSORT diagram is important for reporting accuracy.
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.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.