Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.

Name: Kaimen Rigor review — A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.
Item: A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.
Rating: 59
Author: Alpha1

Xu Z, Ren F, Wang P, Cao J, Tan C, Ma D, Zhao L, Dai J, Ding Y, Fang H, Li H, Liu H, Luo F, Meng Y, Pan P, Xiang P, Xiao Z, Rao S, Satler C, Liu S, Lv Y, Zhao H, Chen S, Cui H, Korzinkin M, Gennert D, Zhavoronkov A

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Kaimen Rigor review — 1.75★ (Critical), 0 critical, 6 high issues for “A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.

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DOI

10.1038/s41591-025-03743-2

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.

Paper source

A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

1.75 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
StatisticsStatistic did not reproduce−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
StatisticsPrinted percentage does not match its own count (capped) ×6−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Biggest issues

01Printed percentage does not match its own count
highArithmeticrecomputedFull detail
20.4% does not match the reported count 3/17
“3 in 60 mg QD (20.4%)”
HypokalemiaFind in source
02Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on change in forced vital capacity (FVC), a surrogate endpoint for clinical benefit in IPF. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD demonstrating TNIK inhibition) nor does it cite validated evidence linking FVC changes to improved clinical outcomes such as survival or quality of life. The FVC change is presented as a secondary endpoint, and the paper acknowledges the need for larger trials to confirm efficacy.
“We observed increased forced vital capacity at the highest dosage with a mean change of +98.4 ml (95% confidence interval 10.9 to 185.9) for patients in the 60 mg rentosertib QD group, compared with −20.3 ml (95% confidence interval −116.1 to 75.6) for the…”
Find in source
03Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect size is a mean FVC increase of +98.4 ml in the 60 mg QD group, which is small relative to the normal FVC range (baseline mean ~2.7 L) and may not exceed the minimal clinically important difference (MCID) for FVC in IPF (2-6% change). The paper mentions that the percentage change met the MCID, but the absolute change is modest and the confidence interval is wide. No anchor to clinical meaningfulness is provided beyond this.
“Patients receiving 60 mg rentosertib QD experienced a mean increase in FVC percentage change of 2.82% by our modeling, meeting the minimal clinically important difference (MCID) reported for FVC in IPF of 2–6% (ref. ).”
Find in source
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
17% does not match the reported count 3/18
“3/18 (17%) in the 60 mg QD group”
Liver injury or dysfunctionFind in source
05Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
77% does not match the reported count 55/71
“55 (77%) completed the 12-week placebo-controlled period”
Completed 12-week periodFind in source
06Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
88% does not match the reported count 15/17
“15 (88%) in the placebo group”
Completed 12-week periodFind in source

4 further findings of this severity or below — every one is in the sections below, filed under its error type.

Findings by category

301ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit5 minor suggestions

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.

This is a well-conducted phase 2a randomized controlled trial with strong scientific premise, rigorous design, and transparent reporting. The main weaknesses are the lack of a formal efficacy power calculation, some threshold-based p-value reporting, and minor internal inconsistencies in the safety results.

Both reviewers classified the study as interventional, and I adopted that classification. The evaluation covered the full text, with all eight dimensions scored. Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification component could only recompute a subset of tests; 7 of 8 were inconsistent, but the coverage note limits interpretation, and no specific errors were identified.

Numerical inconsistencies

3 findings · worst high

Values 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.

Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks. 1 reported summary statistic mathematically impossible for the stated N (PERCENT). 6 printed percentages that do not match their own count.

Overstated conclusions

3 findings · worst high

Conclusions 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

5 major claims checked against the paper's own evidence: 3 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

1 finding · worst medium

An 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.

Other integrity concernAssessed

3 integrity concerns flagged (0 high).

Reporting gaps

None found

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction extensively cites prior research on AI in drug discovery, TNIK's role in IPF, and the limitations of current therapies. It explicitly acknowledges the high failure rate of AI-discovered drugs in phase 2 trials and the lack of phase 3 successes, framing the study as addressing this gap. The rationale for targeting TNIK and testing rentosertib is logically derived from prior evidence, and the study aims to address the limitation of prior work by conducting a randomized controlled trial.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a strong scientific premise by citing prior work on AI-driven drug discovery, TNIK as a target, and the unmet need in IPF, with a clear rationale linking these to the study objectives.

Evidence

paraphrase[Main, paragraph 2]

“AI-discovered drugs have experienced similar levels of phase 2 trial failure as non-AI-discovered drugs, and none has so far progressed through phase 3 trials.”

paraphrase[Main, paragraph 3]

“our group used generative AI-driven discovery tools, to identify Traf2- and Nck-interacting kinase (TNIK) de novo as a critical regulator of idiopathic pulmonary fibrosis (IPF) pathology”

“Here, we present the results of a phase 2a multicenter, double-blind, randomized, placebo-controlled trial to assess the safety, tolerability, PK and impact on FVC of rentosertib”

Main, paragraph 5Find in source

PASSReviewer 2· 90% conf

Evidence

paraphrase[Introduction, paragraphs 1-3]

“Despite these advancements, few AI-discovered or AI-designed drugs have reached clinical trials. AI-discovered drugs have experienced similar levels of phase 2 trial failure as non-AI-discovered drugs, and none has so far progressed through phase 3 trials.”

paraphrase[Introduction, paragraph 3]

“our group used generative AI-driven discovery tools, to identify Traf2- and Nck-interacting kinase (TNIK) de novo as a critical regulator of idiopathic pulmonary fibrosis (IPF) pathology as it orchestrates multiple profibrotic and proinflammatory cellular programs.”

“Here, we present the results of a phase 2a multicenter, double-blind, randomized, placebo-controlled trial to assess the safety, tolerability, PK and impact on FVC of rentosertib at a range of doses for up to 12 weeks in patients with IPF.”

Introduction ¶4Find in source

Randomization was performed via interactive response technology in a 1:1:1:1 ratio, and blinding was comprehensive, covering subjects, investigators, and study staff. Inclusion/exclusion criteria are detailed. The power analysis is based on safety feasibility (90% probability of observing at least one AE with 15 subjects per arm), which is appropriate for a phase 2a safety trial, though not a formal efficacy power calculation. Outlier handling is addressed through the pre-specified analysis population and multiple imputation for missing data.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The trial design is rigorous with adequate randomization, blinding, and pre-specified inclusion/exclusion criteria, though the power analysis is based on safety feasibility rather than efficacy.

Evidence

“Adults with IPF were randomly assigned in a 1:1:1:1 ratio via interactive response technology”

MethodsFind in source

“Subjects, investigators, site study staff, reviewers and everyone involved in study conduct or analysis were blinded with regard to the randomized treatment assignments until after data freeze.”

MethodsFind in source

“Given an approximate sample size of 15 subjects per treatment arm, there exists a 90% probability of observing at least one AE if the true population rate is approximately 15%, which was sufficient to assess the feasibility of safety parameters, although a sample size calculation based on statistical power considerations was not performed.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The trial design is rigorous with adequate randomization, blinding, and pre-specified inclusion/exclusion criteria, though the power analysis is informal and based on safety rather than efficacy.

Evidence

“Adults with IPF were randomly assigned in a 1:1:1:1 ratio via interactive response technology to receive oral rentosertib (at a dose of 30 mg (QD), 30 mg (BID) or 60 mg (QD)) or placebo (QD) for 12 weeks”

MethodsFind in source

“Subjects, investigators, site study staff, reviewers and everyone involved in study conduct or analysis were blinded with regard to the randomized treatment assignments until after data freeze.”

MethodsFind in source

“Given an approximate sample size of 15 subjects per treatment arm, there exists a 90% probability of observing at least one AE if the true population rate is approximately 15%, which is sufficient to assess the feasibility of safety parameters.”

MethodsFind in source

Sex, age, weight, BMI, and race are reported in Table 1. The study enrolled both sexes, so sex_justified is not applicable. Age, weight, and health status are reported. Demographics are reported, including race (all Asian) and smoking history. Species/strain and housing conditions are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are well reported for a human trial, including sex, age, weight, BMI, and demographics, with adequate detail on baseline characteristics.

Evidence

“Male sex – no. (%) | 18 (100.0) | 15 (83.3) | 16 (88.9) | 15 (88.2) | 64 (90.1)”

Table 1Find in source

paraphrase[Table 1]

“Race – no. (%) | Asian | 18 (100.0) | 18 (100.0) | 18 (100.0) | 17 (100.0) | 71 (100.0)”

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial, including sex, age, weight, BMI, and demographics, with adequate detail.

Evidence

“Male sex – no. (%) | 18 (100.0) | 15 (83.3) | 16 (88.9) | 15 (88.2) | 64 (90.1)”

Table 1Find in source

paraphrase[Table 1]

“Race – no. (%) | Asian | 18 (100.0) | 18 (100.0) | 18 (100.0) | 17 (100.0) | 71 (100.0)”

The paper states that the trial was conducted following the Declaration of Helsinki and ICH-GCP guidelines, and that the institutional review board or ethics committee at participating centers approved protocols. Written informed consent was obtained from all patients. This satisfies the requirements for human research.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approvals are adequately reported: the trial was conducted per Declaration of Helsinki and ICH-GCP, with IRB/ethics committee approval and written informed consent.

Evidence

“The institutional review board or ethics committee at participating centers approved protocols and adhered to local laws before initiation of the clinical trial.”

MethodsFind in source

“All patients in this study provided written informed consent.”

MethodsFind in source

“The trial was conducted following the principles outlined in the Declaration of Helsinki and the International Council for Harmonization guidelines for Good Clinical Practice.”

MethodsFind in source

PASSReviewer 2· 90% conf

Ethical approvals are adequately reported with a named ethics committee, informed consent, and regulatory compliance.

Evidence

“The institutional review board or ethics committee at participating centers approved protocols and adhered to local laws before initiation of the clinical trial. All patients in this study provided written informed consent.”

MethodsFind in source

“The trial was conducted following the principles outlined in the Declaration of Helsinki and the International Council for Harmonization guidelines for Good Clinical Practice.”

MethodsFind in source

Rentosertib is identified as the investigational drug, with doses and regimen specified. The sponsor (Insilico Medicine) is named. Software tools for analysis (lme4, clusterProfiler, lm) are identified. Antibodies, cell lines, mycoplasma, and organisms are not applicable as this is a clinical trial without wet-lab assays.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product (rentosertib) is adequately identified, and software tools are identified; other bench resources are not applicable.

Evidence

“receive oral rentosertib (at a dose of 30 mg (QD), 30 mg (BID) or 60 mg (QD)) or placebo (QD) for 12 weeks”

MethodsFind in source

“The lme4 package was used for the generalized linear mixed model analysis.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The investigational product (rentosertib) is adequately identified, and software tools are named, though some details like lot numbers are not provided.

Evidence

“The study treatment rentosertib was provided by Insilico Medicine or a designated contract research organization”

MethodsFind in source

“The lme4 package was used for the generalized linear mixed model analysis.”

Statistical analysisFind in source

Statistical tests are named (ANCOVA, mixed model for repeated measures, Spearman correlation, generalized linear mixed model). Assumptions are handled by design (e.g., multiple imputation for missing data). Effect sizes with 95% CIs are reported for FVC changes. Exact p-values are given for some analyses (e.g., LCQ P=0.0495). Software is identified. Data presentation includes per-group n and confidence intervals. Mathematical plausibility checks were not performed due to continuous data and small N, but no obvious errors were noted.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported; exact p-values are provided where applicable.

Evidence

“An analysis of covariance (ANCOVA) model was performed for endpoints including FVC.”

Statistical analysisFind in source

“patients receiving 60 mg rentosertib QD showed improved FVC, with and +98.4 ml (95% CI 10.9 to 185.9)”

ResultsFind in source

“our modeling indicated a significant increase of least-squares mean change of the LCQ scores of patients receiving 60 mg rentosertib compared with those receiving placebo (two-sided P = 0.0495)”

ResultsFind in source

PASSReviewer 2· 80% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported, though some p-values are reported as thresholds.

Evidence

“patients receiving 60 mg rentosertib QD showed improved FVC, with and +98.4 ml (95% CI 10.9 to 185.9)”

ResultsFind in source

“20, 82 and 192 proteins significantly changing with treatment at weeks 2, 4 and 12, respectively (Benjamini–Hochberg-adjusted P value <0.1)”

ResultsFind in source

The data availability statement provides a concrete route: deidentified Olink proteomics and FVC data deposited at OMIX with accession OMIX008341. Study protocol and SAP available upon request. Custom code is available on GitHub. This meets the criteria for adequate data and code sharing.

Sub-criteria

code sharingADEQUATE

accession numbersADEQUATE

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data and code availability are well-documented: proteomics and FVC data deposited in OMIX with accession, and custom code on GitHub.

Evidence

“Complete deidentified Olink proteomics data, and FVC data, have been deposited at the OMIX database under accession codes at OMIX008341 ( https://ngdc.cncb.ac.cn/omix/release/OMIX008341 ).”

Data availabilityFind in source

“Custom code used to analyze Olink proteomics data is available via GitHub at https://github.com/HUICUI1992/Code-for-NM .”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data and code availability are well addressed with a concrete repository deposit and code sharing, though the data availability statement is somewhat vague for clinical data.

Evidence

“Complete deidentified Olink proteomics data, and FVC data, have been deposited at the OMIX database under accession codes at OMIX008341 ( https://ngdc.cncb.ac.cn/omix/release/OMIX008341 ).”

Data availabilityFind in source

“Custom code used to analyze Olink proteomics data is available via GitHub at https://github.com/HUICUI1992/Code-for-NM .”

Data availabilityFind in source

The trial is registered at ClinicalTrials.gov (NCT05938920). Methods are detailed enough for replication. Limitations are explicitly discussed (small cohort, homogeneity, short follow-up). Conclusions are proportional, noting the need for larger trials. Funding and competing interests are declared. Reporting guideline adherence is implied by Nature Portfolio reporting summary.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Reporting is transparent: trial registered, methods detailed, limitations discussed, and conclusions proportional, with funding and COI statements.

Evidence

“ClinicalTrials.gov registration number: NCT05938920”

AbstractFind in source

“The limitations of this study include the small cohort size of each arm, the geographical and demographic homogeneity of the participants (all were residents of China of similar race) and a short period of follow-up”

DiscussionFind in source

“F.R., S.R., C.S., S.L., Y.L., H.Z., S.C., H.C., M.K., D.G. and A.Z. are employees of Insilico Medicine. Insilico Medicine was the study sponsor.”

Competing interestsFind in source

PASSReviewer 2· 85% conf

Reporting is transparent with trial registration, detailed methods, and discussion of limitations, though a reporting guideline is not explicitly mentioned.

Evidence

“ClinicalTrials.gov registration number: NCT05938920”

AbstractFind in source

DiscussionFind in source

Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

References 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 70 references by DOI: 68 verified — 2 no DOI (shown, not verified).

3 data/code links checked; 3 live.

Copyediting

5 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 5 minor suggestions below.

5 copyedit issues flagged: mostly consistency, typo, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is generally robust, but an informed reader should weigh the retrospective registration (submitted after study start), the lack of a formal efficacy power calculation, and the internal inconsistencies in the safety results (e.g., 20.4% vs 16.7% for 3/18). These issues warrant a correction or independent re-analysis to confirm the reported findings.

1.
HIGHrigor
Correct the internal inconsistency in the primary safety endpoint: the percentage for 3 out of 18 in the 60 mg QD group for hypokalemia is reported as 20.4% but should be 16.7%.
An impossible percentage (3/18 = 16.7%, not 20.4%) is a demonstrable error that undermines the credibility of the safety data.
2.
HIGHrigor
Resolve the duplicate listing of ALT increase for the 60 mg QD group, which appears twice with different counts (6 and 3).
The duplicate and inconsistent counts for the same adverse event in the same dose group is an internal contradiction that must be clarified.
3.
HIGHreporting
Add a statement in the Methods or Reporting Summary explicitly noting adherence to the CONSORT reporting guideline, or justify its absence.
Explicit reporting guideline adherence is expected for randomized trials and improves transparency.
4.
HIGHstatistics
Provide exact p-values for all primary and secondary analyses instead of threshold-based reporting (e.g., 'P < 0.1').
Threshold-based p-values are imprecise and hinder readers' ability to assess the strength of evidence.
5.
HIGHstatistics
Include a formal sample size calculation based on the primary efficacy endpoint (FVC change) in the Methods.
The current power analysis is based on safety feasibility only, which is insufficient for interpreting efficacy results.
6.
HIGHethics
Clarify the timing of trial registration relative to study start; NCT05938920 was first submitted on 2023-06-28, after the study start date of 2023-06-19.
Retrospective registration undermines the pre-specification of outcomes and should be acknowledged or corrected.
7.
MEDIUMcopyedit
Fix the typo in the Abstract: 'with and +98.4 ml' should be 'with +98.4 ml'.
The extra 'and' is a grammatical error that detracts from the manuscript's professionalism.
8.
MEDIUMreporting
Specify the names of the institutional review boards or ethics committees that approved the study, with protocol numbers.
Providing specific IRB names and protocol numbers strengthens the ethics statement.
9.
MEDIUMdata code
Clarify the data availability statement for clinical data by specifying the access mechanism and conditions for requesting the study protocol and SAP.
The current statement says 'available upon request' without details, which is vague for clinical data sharing.
10.
MEDIUMstatistics
Report the exact version numbers of statistical software packages used (e.g., R version, lme4 version) in the Methods.
Version numbers are important for reproducibility.
11.
MEDIUMreporting
Discuss the potential impact of the high withdrawal rate (22.5%) on the interpretation of results.
A high withdrawal rate can bias results, and its impact should be explicitly addressed.
12.
LOWreporting
Clarify the handling of missing data for endpoints other than FVC (e.g., DLCO, 6MWD).
The multiple imputation is described for FVC, but other endpoints may have different missing data handling.
13.
LOWstatistics
Provide a more detailed description of the multiple imputation model used for missing FVC data.
Details on the imputation model (e.g., variables included, number of imputations) would improve transparency.
14.
LOWdata code
Consider providing individual patient data in a repository with controlled access, as is standard for clinical trials.
Sharing IPD would enhance reproducibility and secondary analyses.

Full text (54,469 chars)Analyzed: Aug 15, 2026

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A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.

Read full text (PMC)

DOI

10.1038/s41591-025-03743-2

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Record fingerprint

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Verify via API

Issued Aug 15, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

1.75 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
StatisticsStatistic did not reproduce−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
StatisticsPrinted percentage does not match its own count (capped) ×6−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Biggest issues

01Printed percentage does not match its own count
highArithmeticrecomputedFull detail
20.4% does not match the reported count 3/17
“3 in 60 mg QD (20.4%)”
HypokalemiaFind in source
02Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on change in forced vital capacity (FVC), a surrogate endpoint for clinical benefit in IPF. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD demonstrating TNIK inhibition) nor does it cite validated evidence linking FVC changes to improved clinical outcomes such as survival or quality of life. The FVC change is presented as a secondary endpoint, and the paper acknowledges the need for larger trials to confirm efficacy.
“We observed increased forced vital capacity at the highest dosage with a mean change of +98.4 ml (95% confidence interval 10.9 to 185.9) for patients in the 60 mg rentosertib QD group, compared with −20.3 ml (95% confidence interval −116.1 to 75.6) for the…”
Find in source
03Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect size is a mean FVC increase of +98.4 ml in the 60 mg QD group, which is small relative to the normal FVC range (baseline mean ~2.7 L) and may not exceed the minimal clinically important difference (MCID) for FVC in IPF (2-6% change). The paper mentions that the percentage change met the MCID, but the absolute change is modest and the confidence interval is wide. No anchor to clinical meaningfulness is provided beyond this.
“Patients receiving 60 mg rentosertib QD experienced a mean increase in FVC percentage change of 2.82% by our modeling, meeting the minimal clinically important difference (MCID) reported for FVC in IPF of 2–6% (ref. ).”
Find in source
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
17% does not match the reported count 3/18
“3/18 (17%) in the 60 mg QD group”
Liver injury or dysfunctionFind in source
05Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
77% does not match the reported count 55/71
“55 (77%) completed the 12-week placebo-controlled period”
Completed 12-week periodFind in source
06Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
88% does not match the reported count 15/17
“15 (88%) in the placebo group”
Completed 12-week periodFind in source

4 further findings of this severity or below — every one is in the sections below, filed under its error type.

Findings by category

301ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit5 minor suggestions

Numerical inconsistencies

3 findings · worst high

Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Overstated conclusions

3 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

5 major claims checked against the paper's own evidence: 3 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

1 finding · worst medium

Other integrity concernAssessed

3 integrity concerns flagged (0 high).

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

paraphrase[Main, paragraph 2]

“AI-discovered drugs have experienced similar levels of phase 2 trial failure as non-AI-discovered drugs, and none has so far progressed through phase 3 trials.”

paraphrase[Main, paragraph 3]

“our group used generative AI-driven discovery tools, to identify Traf2- and Nck-interacting kinase (TNIK) de novo as a critical regulator of idiopathic pulmonary fibrosis (IPF) pathology”

“Here, we present the results of a phase 2a multicenter, double-blind, randomized, placebo-controlled trial to assess the safety, tolerability, PK and impact on FVC of rentosertib”

Main, paragraph 5Find in source

PASSReviewer 2· 90% conf

Evidence

paraphrase[Introduction, paragraphs 1-3]

paraphrase[Introduction, paragraph 3]

Introduction ¶4Find in source

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The trial design is rigorous with adequate randomization, blinding, and pre-specified inclusion/exclusion criteria, though the power analysis is based on safety feasibility rather than efficacy.

Evidence

“Adults with IPF were randomly assigned in a 1:1:1:1 ratio via interactive response technology”

MethodsFind in source

“Subjects, investigators, site study staff, reviewers and everyone involved in study conduct or analysis were blinded with regard to the randomized treatment assignments until after data freeze.”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The trial design is rigorous with adequate randomization, blinding, and pre-specified inclusion/exclusion criteria, though the power analysis is informal and based on safety rather than efficacy.

Evidence

MethodsFind in source

“Subjects, investigators, site study staff, reviewers and everyone involved in study conduct or analysis were blinded with regard to the randomized treatment assignments until after data freeze.”

MethodsFind in source

“Given an approximate sample size of 15 subjects per treatment arm, there exists a 90% probability of observing at least one AE if the true population rate is approximately 15%, which is sufficient to assess the feasibility of safety parameters.”

MethodsFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are well reported for a human trial, including sex, age, weight, BMI, and demographics, with adequate detail on baseline characteristics.

Evidence

“Male sex – no. (%) | 18 (100.0) | 15 (83.3) | 16 (88.9) | 15 (88.2) | 64 (90.1)”

Table 1Find in source

paraphrase[Table 1]

“Race – no. (%) | Asian | 18 (100.0) | 18 (100.0) | 18 (100.0) | 17 (100.0) | 71 (100.0)”

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial, including sex, age, weight, BMI, and demographics, with adequate detail.

Evidence

“Male sex – no. (%) | 18 (100.0) | 15 (83.3) | 16 (88.9) | 15 (88.2) | 64 (90.1)”

Table 1Find in source

paraphrase[Table 1]

“Race – no. (%) | Asian | 18 (100.0) | 18 (100.0) | 18 (100.0) | 17 (100.0) | 71 (100.0)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approvals are adequately reported: the trial was conducted per Declaration of Helsinki and ICH-GCP, with IRB/ethics committee approval and written informed consent.

Evidence

“The institutional review board or ethics committee at participating centers approved protocols and adhered to local laws before initiation of the clinical trial.”

MethodsFind in source

“All patients in this study provided written informed consent.”

MethodsFind in source

“The trial was conducted following the principles outlined in the Declaration of Helsinki and the International Council for Harmonization guidelines for Good Clinical Practice.”

MethodsFind in source

PASSReviewer 2· 90% conf

Ethical approvals are adequately reported with a named ethics committee, informed consent, and regulatory compliance.

Evidence

MethodsFind in source

“The trial was conducted following the principles outlined in the Declaration of Helsinki and the International Council for Harmonization guidelines for Good Clinical Practice.”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product (rentosertib) is adequately identified, and software tools are identified; other bench resources are not applicable.

Evidence

“receive oral rentosertib (at a dose of 30 mg (QD), 30 mg (BID) or 60 mg (QD)) or placebo (QD) for 12 weeks”

MethodsFind in source

“The lme4 package was used for the generalized linear mixed model analysis.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The investigational product (rentosertib) is adequately identified, and software tools are named, though some details like lot numbers are not provided.

Evidence

“The study treatment rentosertib was provided by Insilico Medicine or a designated contract research organization”

MethodsFind in source

“The lme4 package was used for the generalized linear mixed model analysis.”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported; exact p-values are provided where applicable.

Evidence

“An analysis of covariance (ANCOVA) model was performed for endpoints including FVC.”

Statistical analysisFind in source

“patients receiving 60 mg rentosertib QD showed improved FVC, with and +98.4 ml (95% CI 10.9 to 185.9)”

ResultsFind in source

“our modeling indicated a significant increase of least-squares mean change of the LCQ scores of patients receiving 60 mg rentosertib compared with those receiving placebo (two-sided P = 0.0495)”

ResultsFind in source

PASSReviewer 2· 80% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported, though some p-values are reported as thresholds.

Evidence

“patients receiving 60 mg rentosertib QD showed improved FVC, with and +98.4 ml (95% CI 10.9 to 185.9)”

ResultsFind in source

“20, 82 and 192 proteins significantly changing with treatment at weeks 2, 4 and 12, respectively (Benjamini–Hochberg-adjusted P value <0.1)”

ResultsFind in source

Sub-criteria

code sharingADEQUATE

accession numbersADEQUATE

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data and code availability are well-documented: proteomics and FVC data deposited in OMIX with accession, and custom code on GitHub.

Evidence

“Complete deidentified Olink proteomics data, and FVC data, have been deposited at the OMIX database under accession codes at OMIX008341 ( https://ngdc.cncb.ac.cn/omix/release/OMIX008341 ).”

Data availabilityFind in source

“Custom code used to analyze Olink proteomics data is available via GitHub at https://github.com/HUICUI1992/Code-for-NM .”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data and code availability are well addressed with a concrete repository deposit and code sharing, though the data availability statement is somewhat vague for clinical data.

Evidence

“Complete deidentified Olink proteomics data, and FVC data, have been deposited at the OMIX database under accession codes at OMIX008341 ( https://ngdc.cncb.ac.cn/omix/release/OMIX008341 ).”

Data availabilityFind in source

“Custom code used to analyze Olink proteomics data is available via GitHub at https://github.com/HUICUI1992/Code-for-NM .”

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Reporting is transparent: trial registered, methods detailed, limitations discussed, and conclusions proportional, with funding and COI statements.

Evidence

“ClinicalTrials.gov registration number: NCT05938920”

AbstractFind in source

DiscussionFind in source

“F.R., S.R., C.S., S.L., Y.L., H.Z., S.C., H.C., M.K., D.G. and A.Z. are employees of Insilico Medicine. Insilico Medicine was the study sponsor.”

Competing interestsFind in source

PASSReviewer 2· 85% conf

Reporting is transparent with trial registration, detailed methods, and discussion of limitations, though a reporting guideline is not explicitly mentioned.

Evidence

“ClinicalTrials.gov registration number: NCT05938920”

AbstractFind in source

DiscussionFind in source

Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

References 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 70 references by DOI: 68 verified — 2 no DOI (shown, not verified).

3 data/code links checked; 3 live.

Copyediting

5 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 5 minor suggestions below.

5 copyedit issues flagged: mostly consistency, typo, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHrigor
Correct the internal inconsistency in the primary safety endpoint: the percentage for 3 out of 18 in the 60 mg QD group for hypokalemia is reported as 20.4% but should be 16.7%.
An impossible percentage (3/18 = 16.7%, not 20.4%) is a demonstrable error that undermines the credibility of the safety data.
2.
HIGHrigor
Resolve the duplicate listing of ALT increase for the 60 mg QD group, which appears twice with different counts (6 and 3).
The duplicate and inconsistent counts for the same adverse event in the same dose group is an internal contradiction that must be clarified.
3.
HIGHreporting
Add a statement in the Methods or Reporting Summary explicitly noting adherence to the CONSORT reporting guideline, or justify its absence.
Explicit reporting guideline adherence is expected for randomized trials and improves transparency.
4.
HIGHstatistics
Provide exact p-values for all primary and secondary analyses instead of threshold-based reporting (e.g., 'P < 0.1').
Threshold-based p-values are imprecise and hinder readers' ability to assess the strength of evidence.
5.
HIGHstatistics
Include a formal sample size calculation based on the primary efficacy endpoint (FVC change) in the Methods.
The current power analysis is based on safety feasibility only, which is insufficient for interpreting efficacy results.
6.
HIGHethics
Clarify the timing of trial registration relative to study start; NCT05938920 was first submitted on 2023-06-28, after the study start date of 2023-06-19.
Retrospective registration undermines the pre-specification of outcomes and should be acknowledged or corrected.
7.
MEDIUMcopyedit
Fix the typo in the Abstract: 'with and +98.4 ml' should be 'with +98.4 ml'.
The extra 'and' is a grammatical error that detracts from the manuscript's professionalism.
8.
MEDIUMreporting
Specify the names of the institutional review boards or ethics committees that approved the study, with protocol numbers.
Providing specific IRB names and protocol numbers strengthens the ethics statement.
9.
MEDIUMdata code
Clarify the data availability statement for clinical data by specifying the access mechanism and conditions for requesting the study protocol and SAP.
The current statement says 'available upon request' without details, which is vague for clinical data sharing.
10.
MEDIUMstatistics
Report the exact version numbers of statistical software packages used (e.g., R version, lme4 version) in the Methods.
Version numbers are important for reproducibility.
11.
MEDIUMreporting
Discuss the potential impact of the high withdrawal rate (22.5%) on the interpretation of results.
A high withdrawal rate can bias results, and its impact should be explicitly addressed.
12.
LOWreporting
Clarify the handling of missing data for endpoints other than FVC (e.g., DLCO, 6MWD).
The multiple imputation is described for FVC, but other endpoints may have different missing data handling.
13.
LOWstatistics
Provide a more detailed description of the multiple imputation model used for missing FVC data.
Details on the imputation model (e.g., variables included, number of imputations) would improve transparency.
14.
LOWdata code
Consider providing individual patient data in a repository with controlled access, as is standard for clinical trials.
Sharing IPD would enhance reproducibility and secondary analyses.

Full text (54,469 chars)Analyzed: Aug 15, 2026