Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.

Name: Kaimen Rigor review — TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.
Item: TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.
Rating: 96
Author: Alpha1

Noureddin M, Alkhouri N, Lawitz EJ, Kowdley KV, Loomba R, Lee L, Jones C, Schlegel A, Marmon T, Anderson K, Li Y, Quirk E, Harrison SA

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Kaimen Rigor review — 2.25★ (Weak), 0 critical, 4 high issues for “TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.”

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

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TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.

Noureddin M, Alkhouri N, Lawitz EJ, Kowdley KV, Loomba R, Lee L, Jones C, Schlegel A, Marmon T, Anderson K, Li Y, Quirk E, Harrison SA

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DOI

10.1038/s41591-025-03722-7

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.

Noureddin M, Alkhouri N, Lawitz EJ, Kowdley KV, Loomba R, Lee L, Jones C, Schlegel A, Marmon T, Anderson K, Li Y, Quirk E, Harrison SA

Paper source

TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.

Read full text (PMC)

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

2.25 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability partially met−0.25★

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

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is MRI-PDFF, a surrogate for liver fat content, not a hard clinical outcome. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD showing receptor occupancy) nor cite validated evidence linking MRI-PDFF reduction to clinical outcomes such as mortality or cirrhosis. Although the discussion mentions associations with histologic response, this is not a validated surrogate for clinical benefit.
“The primary endpoint was relative change from baseline at week 12 in liver fat content with TERN-501 monotherapy versus placebo, using magnetic resonance imaging proton density fat fraction (MRI-PDFF).”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect is a reduction in liver fat content (MRI-PDFF) of up to 44.8% relative to baseline, but this is a surrogate biomarker change. The paper does not anchor this to a minimal clinically important difference or demonstrate that it translates to improved clinical outcomes. The effect size is presented as statistically significant but lacks clinical meaningfulness.
“Least squares mean (s.e.) changes from baseline at week 12 in MRI-PDFF with TERN-501 were: −15.4% (5.2%) with 1 mg, −27.5% (5.7%) with 3 mg (P = 0.0036) and −44.8% (5.9%) with 6 mg (P < 0.0001), versus −4.0% (5.4%) with placebo.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit7 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 and transparently reported phase 2a randomized controlled trial with rigorous design, clear ethical approvals, and appropriate statistical methods. The main weakness is the vague data availability statement and lack of code sharing, which limits reproducibility. Minor internal inconsistencies and copyedit issues (e.g., drug name typo, p-value discrepancy) should be corrected.

Both reviewers agreed on study type (interventional) and on all dimension statuses except a minor divergence on reporting guideline (Reviewer 2 flagged it as inadequate, Reviewer 1 as adequate). The statistics verification recomputed only 2 tests (both consistent); other reported statistics were not machine-verified. The citation check found no retracted or unresolved references. The integrity check flagged three low-severity internal inconsistencies (see action items).

Numerical inconsistencies

1 finding · worst low

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.

Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.

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: 2 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

None found

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.

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

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.

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

The introduction thoroughly reviews the pathophysiology of MASH, the role of THRβ agonism, and prior clinical data on resmetirom and TERN-501, establishing a strong rationale. Limitations of prior research are implicitly addressed by noting the need for additional THRβ agonists with favorable safety and PK profiles, and the rationale for combination therapy is clearly articulated.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study builds on a well-established scientific premise with extensive prior work and a clear rationale for testing TERN-501 alone and in combination.

Evidence

“Thyroid hormone receptor-β (THRβ) agonism is a validated mechanism for treating metabolic dysfunction-associated steatohepatitis (MASH).”

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 4]

“Due to the multifactorial pathophysiology of MASLD and MASH, combination approaches may be necessary to maximize response to pharmacological intervention.”

“there remains a need for additional THRβ agonist treatment options with favorable safety and drug–drug interaction profiles, and reduced pharmacokinetic (PK) variability.”

Introduction ¶4Find in source

PASSReviewer 2· 95% conf

The study builds on a well-established scientific premise with extensive prior work cited and a clear rationale for the study objectives.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“In studies of patients with noncirrhotic MASH, pharmacological THRβ agonism resulted in MASH resolution and fibrosis regression.”

paraphrase[Introduction, paragraph 4]

“Due to the multifactorial pathophysiology of MASLD and MASH, combination approaches may be necessary to maximize response to pharmacological intervention.”

“there remains a need for additional THRβ agonist treatment options with favorable safety and drug–drug interaction profiles, and reduced pharmacokinetic (PK) variability.”

Introduction ¶4Find in source

Randomization used an interactive web response system with a 1:1:1:1:1:1:1 ratio. Blinding of patients, investigators, and study personnel is stated. A power analysis is provided for the primary endpoint. Inclusion/exclusion criteria are detailed. The analysis populations (efficacy, safety, PK/PD) are defined. Outlier handling is addressed through the pre-specified analysis population and missing data approach (no imputation for primary analysis).

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· 95% conf

The trial design is rigorous: randomized, double-blind, placebo-controlled, with pre-specified endpoints, sample size calculation, and clear inclusion/exclusion criteria.

Evidence

“An interactive web response system was used to randomize patients in a 1:1:1:1:1:1:1 ratio to TERN-501 1 mg, TERN-501 3 mg, TERN-501 6 mg, TERN-101 10 mg, TERN-501 3 mg plus TERN-101 10 mg, TERN-501 6 mg plus TERN-101 10 mg or matching placebo.”

MethodsFind in source

“Patients, investigators and study personnel were masked to treatment assignment during the study.”

MethodsFind in source

“Based on an assumed pooled SD of 22% with a two-sided alpha of 0.05, a mean relative reduction difference in MRI-PDFF at week 12 of 23% between TERN-501 monotherapy and placebo would provide approximately 90% power”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The study design is rigorous with adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

MethodsFind in source

“Patients, investigators and study personnel were masked to treatment assignment during the study.”

MethodsFind in source

Statistical analysisFind in source

Sex is reported for all patients (54.9% female), and age, BMI, and health status (including T2D, hypertension, dyslipidemia) are detailed in Table 1. Since both sexes are enrolled, sex_justified is not applicable. Demographics include race and ethnicity. 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

Demographic and clinical characteristics are comprehensively reported, including sex, age, BMI, comorbidities, and baseline labs.

Evidence

paraphrase[Table 1]

“Sex, n (%) | Male 73 (45.1) | Female 89 (54.9)”

paraphrase[Results, Study design and patients]

“Overall, mean (s.d.) age was 53.3 (11.8) years and 54.9% were female. ... Mean (s.d.) body mass index was 37.8 (6.9) kg m −2 .”

PASSReviewer 2· 95% conf

Demographic and clinical characteristics are comprehensively reported, including sex, age, BMI, and comorbidities.

Evidence

“Overall, mean (s.d.) age was 53.3 (11.8) years and 54.9% were female.”

ResultsFind in source

“Most patients were white (85.8%) and were Hispanic or Latino (61.1%).”

ResultsFind in source

“T2D, n (%) | 11 (45.8) | 8 (34.8) | 10 (43.5) | 6 (27.3) | 7 (29.2) | 13 (56.5) | 13 (56.5) | 68 (42.0)”

Table 1Find in source

The study states it was conducted in accordance with ICH GCP and the Declaration of Helsinki, and that the protocol was approved by the institutional review board or independent ethics committee at each study center. All patients provided written informed consent. Regulatory compliance is explicitly stated.

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 approval and informed consent are adequately documented.

Evidence

“The protocol and subsequent amendments, and other relevant documents, were approved by the institutional review board or independent ethics committee at each study center”

MethodsFind in source

“All patients provided written informed consent before enrollment.”

MethodsFind in source

“The study was conducted in accordance with the applicable International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approval and informed consent are adequately documented.

Evidence

“The protocol and subsequent amendments, and other relevant documents, were approved by the institutional review board or independent ethics committee at each study center”

MethodsFind in source

“All patients provided written informed consent before enrollment.”

MethodsFind in source

“The study was conducted in accordance with the applicable International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki”

MethodsFind in source

TERN-501 and TERN-101 are named as investigational drugs with their mechanisms and doses. The study is a drug trial, so antibodies, cell lines, mycoplasma, and organisms are not applicable. Reagents are scored against the investigational products, which are adequately described. Software tools (SAS v.9.4, Phoenix WinNonlin v.8.3.5) are identified.

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 drugs are adequately identified, and statistical software is named.

Evidence

“TERN-501 monotherapy (1 mg ( n = 23), 3 mg ( n = 23) or 6 mg ( n = 22)), TERN-101 10-mg monotherapy ( n = 24)”

AbstractFind in source

“Data analysis was performed using SAS v.9.4.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational products (TERN-501 and TERN-101) are adequately identified, and statistical software is specified.

Evidence

“TERN-501 (THRβ agonist) as monotherapy or combined with TERN-101 (farnesoid X receptor agonist)”

AbstractFind in source

“Data analysis was performed using SAS v.9.4.”

Statistical analysisFind in source

“Noncompartmental PK parameters were estimated from individual plasma concentration data using Phoenix WinNonlin v.8.3.5.”

Statistical analysisFind in source

The primary analysis uses ANCOVA with treatment group and baseline as covariates. Tests are named (ANCOVA, chi-square). Exact p-values are reported (e.g., P = 0.0036). Effect sizes are reported as LS means with s.e. and 95% CIs. Software is identified. Data presentation includes per-group n and error bars defined as s.e. or s.d. Mathematical plausibility checks were not performed due to continuous outcomes and large N, but no obvious inconsistencies 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· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes with CIs.

Evidence

“Statistical analysis was performed using a type III sum of squares ANCOVA model with treatment group as a fixed effect and baseline value as the covariate”

Figure 2Find in source

“The LS mean differences were statistically significant compared to placebo for the TERN-501 3-mg ( P = 0.0036) and 6-mg ( P < 0.0001) treatment groups”

ResultsFind in source

“Estimates of the LS mean difference between treatment groups and placebo are presented with the associated s.e. of the difference, 95% CI of the difference and pairwise comparisons.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes with CIs reported.

Evidence

“Efficacy endpoints (cT1 and MRI-PDFF analyses) used an analysis of covariance (ANCOVA) model with relative change from baseline at week 12 as the dependent variable including treatment group as a fixed effect and baseline as the covariate”

Statistical analysisFind in source

“The LS mean differences were statistically significant compared to placebo for the TERN-501 3-mg ( P = 0.0036) and 6-mg ( P < 0.0001) treatment groups”

ResultsFind in source

“Estimates of the LS mean difference between treatment groups and placebo are presented with the associated s.e. of the difference, 95% CI of the difference and pairwise comparisons.”

Statistical analysisFind in source

The data availability statement says data are not publicly available but requests will be considered on a case-by-case basis 3 years after publication, with conditions. This is reported_but_inadequate because it lacks a concrete mechanism or platform. Repository deposit and accession numbers are not applicable for patient-level data. Code availability is stated as 'Not applicable', which is acceptable if no bespoke code was used, but the statistical analysis code is not shared.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

A data availability statement exists but is vague, and no code is shared.

Evidence

“Requests for data supporting the findings in this manuscript should be made to the corresponding author (M.N.: NoureddinMD@houstonresearchinstitute.com) and will be considered on a case-by-case basis 3 years after publication.”

Data availabilityFind in source

“Code availability Not applicable.”

Data availabilityFind in source

WARNReviewer 2· 90% conf

A data availability statement is present but vague, and no code is shared.

Evidence

Data availabilityFind in source

“Code availability Not applicable.”

Data availabilityFind in source

The trial is registered (NCT05415722). Methods are detailed enough for replication. A reporting guideline (CONSORT) is implied by the flow diagram, though not explicitly referenced. All pre-specified outcomes are reported, including negative results. Limitations are discussed. Conclusions are proportional to the evidence. Funding and COI are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent: registered, reports all outcomes, discusses limitations, and provides funding/COI statements.

Evidence

“ClinicalTrials.gov registration: NCT05415722”

AbstractFind in source

“Our study had a small sample size that resulted in baseline imbalance in some treatment groups, including in presence of T2D, hypertension and statin use.”

DiscussionFind in source

“The study was funded by Terns Pharmaceuticals.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

The manuscript is transparent with trial registration, detailed methods, and discussion of limitations.

Evidence

“ClinicalTrials.gov registration: NCT05415722”

AbstractFind in source

“Our study had a small sample size that resulted in baseline imbalance in some treatment groups, including in presence of T2D, hypertension and statin use.”

DiscussionFind in source

“The study was funded by Terns Pharmaceuticals.”

AcknowledgementsFind in source

Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

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 54 references by DOI: 42 verified — 12 no DOI (shown, not verified).

2 data/code links checked; 2 live.

Copyediting

7 minor

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

No major wording or formatting errors. 7 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and generally trustworthy, but an informed reader should weigh the vague data availability statement and the minor internal inconsistencies (e.g., p-value discrepancy, site count mismatch). These do not invalidate the conclusions but warrant a correction or clarification from the authors.

1.
HIGHstatistics
Reconcile the p-value for TERN-501 1 mg in Figure 3b (P = 0.9645) with the text (P = 0.09645) and correct the erroneous value.
An internal contradiction in a reported p-value undermines statistical credibility and could mislead readers.
2.
HIGHreporting
Clarify the discrepancy between the Methods stating 35 centers and the Results stating 27 sites enrolled patients.
An internal inconsistency in the number of study sites raises questions about data accuracy.
3.
HIGHreporting
Clarify the statement 'Of the 140 patients to be randomized' in the Methods, which conflicts with the abstract's '162 patients were randomized'.
This internal contradiction could confuse readers about the actual sample size and randomization plan.
4.
HIGHdata code
Replace the vague data availability statement with a concrete access mechanism (e.g., a named data access committee or platform like Vivli) and specify the review process and timeline.
A vague 'on request' statement is insufficient for reproducibility and is a common reviewer concern.
5.
MEDIUMdata code
Share the statistical analysis code (e.g., SAS scripts) in a public repository, or explicitly state that no bespoke code was used beyond standard SAS procedures.
Sharing code enhances reproducibility and transparency, even if patient-level data cannot be shared.
6.
MEDIUMreporting
Explicitly reference the CONSORT reporting guideline in the Methods or Reporting Summary.
Explicitly naming the guideline strengthens transparency and compliance with reporting standards.
7.
MEDIUMcopyedit
Fix the typo 'TERN-510 monotherapy' to 'TERN-501 monotherapy' in the Methods, Statistical analysis section.
A drug name typo could cause confusion and appears unprofessional.
8.
MEDIUMcopyedit
Correct the p-value formatting inconsistency in Figure 3 legend and Results (P = 0.09645 vs P = 0.0965 or P = 0.9645).
Inconsistent decimal places in p-values are a copyedit issue that could be misread.
9.
MEDIUMcopyedit
Fix the missing space in 'heartrates' to 'heart rates' in the Results, Safety section.
Typographical errors detract from the manuscript's professionalism.
10.
LOWcopyedit
Rephrase the abstract sentence 'TERN-501 (3 mg ( n = 23) or 6 mg ( n = 23)) plus TERN-101 10-mg combination therapy' for clarity, e.g., 'TERN-501 (3 mg or 6 mg) plus TERN-101 10-mg combination therapy'.
The current phrasing is redundant and slightly awkward.
11.
LOWreporting
Consider adding a statement about sex-based analyses, even if not powered, to address the lack of sex-specific results.
This would strengthen the biological variables reporting and address potential reviewer concerns.

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TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.

Noureddin M, Alkhouri N, Lawitz EJ, Kowdley KV, Loomba R, Lee L, Jones C, Schlegel A, Marmon T, Anderson K, Li Y, Quirk E, Harrison SA

Read full text (PMC)

DOI

10.1038/s41591-025-03722-7

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Record fingerprint

4b8f56f472f5755746b0915bdfd3bcd81cb1e637866e20f884fe79425bb8bf96

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

2.25 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability partially met−0.25★

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

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is MRI-PDFF, a surrogate for liver fat content, not a hard clinical outcome. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD showing receptor occupancy) nor cite validated evidence linking MRI-PDFF reduction to clinical outcomes such as mortality or cirrhosis. Although the discussion mentions associations with histologic response, this is not a validated surrogate for clinical benefit.
“The primary endpoint was relative change from baseline at week 12 in liver fat content with TERN-501 monotherapy versus placebo, using magnetic resonance imaging proton density fat fraction (MRI-PDFF).”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect is a reduction in liver fat content (MRI-PDFF) of up to 44.8% relative to baseline, but this is a surrogate biomarker change. The paper does not anchor this to a minimal clinically important difference or demonstrate that it translates to improved clinical outcomes. The effect size is presented as statistically significant but lacks clinical meaningfulness.
“Least squares mean (s.e.) changes from baseline at week 12 in MRI-PDFF with TERN-501 were: −15.4% (5.2%) with 1 mg, −27.5% (5.7%) with 3 mg (P = 0.0036) and −44.8% (5.9%) with 6 mg (P < 0.0001), versus −4.0% (5.4%) with placebo.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit7 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.

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: 2 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

None found

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study builds on a well-established scientific premise with extensive prior work and a clear rationale for testing TERN-501 alone and in combination.

Evidence

“Thyroid hormone receptor-β (THRβ) agonism is a validated mechanism for treating metabolic dysfunction-associated steatohepatitis (MASH).”

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 4]

“Due to the multifactorial pathophysiology of MASLD and MASH, combination approaches may be necessary to maximize response to pharmacological intervention.”

“there remains a need for additional THRβ agonist treatment options with favorable safety and drug–drug interaction profiles, and reduced pharmacokinetic (PK) variability.”

Introduction ¶4Find in source

PASSReviewer 2· 95% conf

The study builds on a well-established scientific premise with extensive prior work cited and a clear rationale for the study objectives.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“In studies of patients with noncirrhotic MASH, pharmacological THRβ agonism resulted in MASH resolution and fibrosis regression.”

paraphrase[Introduction, paragraph 4]

“Due to the multifactorial pathophysiology of MASLD and MASH, combination approaches may be necessary to maximize response to pharmacological intervention.”

“there remains a need for additional THRβ agonist treatment options with favorable safety and drug–drug interaction profiles, and reduced pharmacokinetic (PK) variability.”

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· 95% conf

The trial design is rigorous: randomized, double-blind, placebo-controlled, with pre-specified endpoints, sample size calculation, and clear inclusion/exclusion criteria.

Evidence

MethodsFind in source

“Patients, investigators and study personnel were masked to treatment assignment during the study.”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The study design is rigorous with adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

MethodsFind in source

“Patients, investigators and study personnel were masked to treatment assignment during the study.”

MethodsFind in source

Statistical analysisFind 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

Demographic and clinical characteristics are comprehensively reported, including sex, age, BMI, comorbidities, and baseline labs.

Evidence

paraphrase[Table 1]

“Sex, n (%) | Male 73 (45.1) | Female 89 (54.9)”

paraphrase[Results, Study design and patients]

“Overall, mean (s.d.) age was 53.3 (11.8) years and 54.9% were female. ... Mean (s.d.) body mass index was 37.8 (6.9) kg m −2 .”

PASSReviewer 2· 95% conf

Demographic and clinical characteristics are comprehensively reported, including sex, age, BMI, and comorbidities.

Evidence

“Overall, mean (s.d.) age was 53.3 (11.8) years and 54.9% were female.”

ResultsFind in source

“Most patients were white (85.8%) and were Hispanic or Latino (61.1%).”

ResultsFind in source

“T2D, n (%) | 11 (45.8) | 8 (34.8) | 10 (43.5) | 6 (27.3) | 7 (29.2) | 13 (56.5) | 13 (56.5) | 68 (42.0)”

Table 1Find in source

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 approval and informed consent are adequately documented.

Evidence

“The protocol and subsequent amendments, and other relevant documents, were approved by the institutional review board or independent ethics committee at each study center”

MethodsFind in source

“All patients provided written informed consent before enrollment.”

MethodsFind in source

“The study was conducted in accordance with the applicable International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approval and informed consent are adequately documented.

Evidence

“The protocol and subsequent amendments, and other relevant documents, were approved by the institutional review board or independent ethics committee at each study center”

MethodsFind in source

“All patients provided written informed consent before enrollment.”

MethodsFind in source

“The study was conducted in accordance with the applicable International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki”

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 drugs are adequately identified, and statistical software is named.

Evidence

“TERN-501 monotherapy (1 mg ( n = 23), 3 mg ( n = 23) or 6 mg ( n = 22)), TERN-101 10-mg monotherapy ( n = 24)”

AbstractFind in source

“Data analysis was performed using SAS v.9.4.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational products (TERN-501 and TERN-101) are adequately identified, and statistical software is specified.

Evidence

“TERN-501 (THRβ agonist) as monotherapy or combined with TERN-101 (farnesoid X receptor agonist)”

AbstractFind in source

“Data analysis was performed using SAS v.9.4.”

Statistical analysisFind in source

“Noncompartmental PK parameters were estimated from individual plasma concentration data using Phoenix WinNonlin v.8.3.5.”

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· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes with CIs.

Evidence

“Statistical analysis was performed using a type III sum of squares ANCOVA model with treatment group as a fixed effect and baseline value as the covariate”

Figure 2Find in source

“The LS mean differences were statistically significant compared to placebo for the TERN-501 3-mg ( P = 0.0036) and 6-mg ( P < 0.0001) treatment groups”

ResultsFind in source

“Estimates of the LS mean difference between treatment groups and placebo are presented with the associated s.e. of the difference, 95% CI of the difference and pairwise comparisons.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes with CIs reported.

Evidence

Statistical analysisFind in source

“The LS mean differences were statistically significant compared to placebo for the TERN-501 3-mg ( P = 0.0036) and 6-mg ( P < 0.0001) treatment groups”

ResultsFind in source

“Estimates of the LS mean difference between treatment groups and placebo are presented with the associated s.e. of the difference, 95% CI of the difference and pairwise comparisons.”

Statistical analysisFind in source

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

A data availability statement exists but is vague, and no code is shared.

Evidence

Data availabilityFind in source

“Code availability Not applicable.”

Data availabilityFind in source

WARNReviewer 2· 90% conf

A data availability statement is present but vague, and no code is shared.

Evidence

Data availabilityFind in source

“Code availability Not applicable.”

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent: registered, reports all outcomes, discusses limitations, and provides funding/COI statements.

Evidence

“ClinicalTrials.gov registration: NCT05415722”

AbstractFind in source

“Our study had a small sample size that resulted in baseline imbalance in some treatment groups, including in presence of T2D, hypertension and statin use.”

DiscussionFind in source

“The study was funded by Terns Pharmaceuticals.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

The manuscript is transparent with trial registration, detailed methods, and discussion of limitations.

Evidence

“ClinicalTrials.gov registration: NCT05415722”

AbstractFind in source

“Our study had a small sample size that resulted in baseline imbalance in some treatment groups, including in presence of T2D, hypertension and statin use.”

DiscussionFind in source

“The study was funded by Terns Pharmaceuticals.”

AcknowledgementsFind in source

Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

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 54 references by DOI: 42 verified — 12 no DOI (shown, not verified).

2 data/code links checked; 2 live.

Copyediting

7 minor

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

No major wording or formatting errors. 7 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHstatistics
Reconcile the p-value for TERN-501 1 mg in Figure 3b (P = 0.9645) with the text (P = 0.09645) and correct the erroneous value.
An internal contradiction in a reported p-value undermines statistical credibility and could mislead readers.
2.
HIGHreporting
Clarify the discrepancy between the Methods stating 35 centers and the Results stating 27 sites enrolled patients.
An internal inconsistency in the number of study sites raises questions about data accuracy.
3.
HIGHreporting
Clarify the statement 'Of the 140 patients to be randomized' in the Methods, which conflicts with the abstract's '162 patients were randomized'.
This internal contradiction could confuse readers about the actual sample size and randomization plan.
4.
HIGHdata code
Replace the vague data availability statement with a concrete access mechanism (e.g., a named data access committee or platform like Vivli) and specify the review process and timeline.
A vague 'on request' statement is insufficient for reproducibility and is a common reviewer concern.
5.
MEDIUMdata code
Share the statistical analysis code (e.g., SAS scripts) in a public repository, or explicitly state that no bespoke code was used beyond standard SAS procedures.
Sharing code enhances reproducibility and transparency, even if patient-level data cannot be shared.
6.
MEDIUMreporting
Explicitly reference the CONSORT reporting guideline in the Methods or Reporting Summary.
Explicitly naming the guideline strengthens transparency and compliance with reporting standards.
7.
MEDIUMcopyedit
Fix the typo 'TERN-510 monotherapy' to 'TERN-501 monotherapy' in the Methods, Statistical analysis section.
A drug name typo could cause confusion and appears unprofessional.
8.
MEDIUMcopyedit
Correct the p-value formatting inconsistency in Figure 3 legend and Results (P = 0.09645 vs P = 0.0965 or P = 0.9645).
Inconsistent decimal places in p-values are a copyedit issue that could be misread.
9.
MEDIUMcopyedit
Fix the missing space in 'heartrates' to 'heart rates' in the Results, Safety section.
Typographical errors detract from the manuscript's professionalism.
10.
LOWcopyedit
Rephrase the abstract sentence 'TERN-501 (3 mg ( n = 23) or 6 mg ( n = 23)) plus TERN-101 10-mg combination therapy' for clarity, e.g., 'TERN-501 (3 mg or 6 mg) plus TERN-101 10-mg combination therapy'.
The current phrasing is redundant and slightly awkward.
11.
LOWreporting
Consider adding a statement about sex-based analyses, even if not powered, to address the lack of sex-specific results.
This would strengthen the biological variables reporting and address potential reviewer concerns.

Full text (74,389 chars)Analyzed: Aug 15, 2026