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Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial

Name: Kaimen Rigor review — Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial
Item: Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial
Rating: 59
Author: Alpha1

Gaudet D, Gonciarz M, Shen X, Leohr JK, Beyer TP, Day JW, Mullins GR, Zhen EY, Hartley M, Larouche M, Konrad RJ, Benichou O, Ruotolo G.

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Kaimen Rigor review — 3.5★ (Adequate), 0 critical, 6 high issues for “Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial”

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Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial

Gaudet D, Gonciarz M, Shen X, Leohr JK, Beyer TP, Day JW, Mullins GR, Zhen EY, Hartley M, Larouche M, Konrad RJ, Benichou O, Ruotolo G.

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DOI

10.1038/s41591-025-03830-4

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial

Gaudet D, Gonciarz M, Shen X, Leohr JK, Beyer TP, Day JW, Mullins GR, Zhen EY, Hartley M, Larouche M, Konrad RJ, Benichou O, Ruotolo G.

Paper source

Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial

Read full text (PMC)

Embed this Rigor badge

Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 10, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

3.5 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ReportingEthical approvals partially met−0.25★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: moderateEngine: 7.29.0Source: full text

Not verified in this report

References were found (48) but none could be checked — every lookup failed or lacked a DOI.
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.

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions · partly checked 103AuthenticityData authenticity concerns 204DisclosureReporting gaps 05AvailabilityNone found 06Copyedit13 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.

The paper reports a well-designed phase 1 trial with a strong scientific premise, transparent reporting, and adequate ethical and resource documentation. However, several methodological and reporting gaps temper the robustness: the randomization method and blinding details are underdescribed, formal power analysis is absent, confidence intervals for main efficacy outcomes are not reported, analysis code is not shared, and the specific IRB is not named. These are common issues in early-phase clinical trial reporting but are flagged here for completeness.

The evaluation is based on the full text of the published paper, with three independent reviews from the same model and a copyedit pass. The statistics verification component checked no tests (coverage note: only tests with test statistic+df or effect+CI are verifiable; none such were present). The citation check found no retracted or unfound references. The preregistration is confirmed. The integrity concerns are low-severity. The paper is a published clinical trial; the assessment is a post-publication robustness audit.

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

Overstated conclusions

1 finding · worst low

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.

Conclusions only partially backed by the presented evidenceAssessed

10 major claims checked against the paper's own evidence: all adequately supported.

Data authenticity concerns

1 finding · worst low

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

2 integrity concerns flagged (0 high).

Reporting gaps

2 findings · 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
Ethics/consent reporting incompleteAssessed

Eight Dimensions6 pass · 2 warn

The introduction reviews the ANGPTL family, ANGPTL3/8 complex biology, and prior ANGPTL3 inhibitors (evinacumab, vupanorsen, zodasiran), highlighting the limitations and the rationale for targeting ANGPTL3/8 specifically. The hypothesis (that LY3475766 will safely reduce atherogenic lipoproteins) follows logically from the cited evidence. The discussion acknowledges limitations of prior work (e.g., HDL-C lowering with ANGPTL3 inhibitors) and positions the current study as addressing those gaps.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific foundation linking the ANGPTL3/8 complex to LPL inhibition and dyslipidemia, and justifies the target and the antibody.

Evidence

“Recent studies on how the ANGPTL protein family modulates LPL activity have identified the mechanisms by which LPL activity is controlled in a tissue-specific manner”

Introduction ¶1Find in source

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target.”

Introduction ¶5Find in source

Discussion ¶5Find in source

PASSReviewer 2· 95% conf

The paper establishes a strong scientific foundation by citing extensive prior work on ANGPTL3/8 and LPL, clearly rationalizing the study, and addressing limitations of previous approaches.

Evidence

paraphrase[Introduction, paragraphs 1-5]

“In recent years, agents inhibiting angiopoietin-like protein 3 (ANGPTL3) have been developed... ANGPTL3 is part of the broad ANGPTL protein family... ANGPTL8 forms localized ANGPTL4/8 complexes in adipose tissue... The ability of ANGPTL3/8 to inhibit LPL activity has been shown to be suppressed by apolipoprotein (Apo)A-V...”

paraphrase[Introduction, paragraph 5]

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target. Therefore, we developed a fully human anti-ANGPTL3/8 antibody, LY3475766...”

paraphrase[Discussion, paragraph 4]

“Recent data from vupanorsen, an ANGPTL3 antisense oligonucleotide (ASO), and zodasiran, an ANGPTL3 small interfering RNA (siRNA), suggest that HDL-C lowering may be a class effect with ANGPTL3 inhibitors... the degree of LDL-C and ApoB lowering achieved with both compounds was less than that observed with evinacumab...”

PASSReviewer 3· 95% conf

The scientific premise is well established through extensive citation of prior work on ANGPTL3/8 biology, LOF variants, and existing inhibitors, with a clear rationale linking the target to the study objectives.

Evidence

“Naturally occurring ANGPTL3 loss-of-function (LOF) variants are associated with lower levels of low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C), and a reduced risk of cardiovascular disease (CVD)”

Main text, paragraphs 1-5Find in source

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target.”

Main text, paragraph 5Find in source

“The effects of ANGPTL3/8 inhibition on HDL metabolism were different from those of ANGPTL3 inhibition (as well as ANGPTL3 LOF mutations), in which a net decrease in HDL-C has been observed”

Discussion ¶4Find in source

The trial is randomized, double-blind, and placebo-controlled across 5 dose cohorts. The randomization unit (individual participant) is clear, inclusion/exclusion criteria are specified, and outlier handling is pre-defined. However, the randomization method (e.g., computer-generated numbers) is not stated, and no a priori power analysis is provided. These are not critical for a phase 1 safety trial but are noted as missing. Blinding is described as double-blind, and the placebo is 0.9% sodium chloride. The 300mg cohort was restarted due to COVID-19, and the handling is transparent.

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodNOT REPORTED

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 75% conf

Core design elements (randomization ratio, unit, blinding, inclusion/exclusion, outlier handling, placebo control) are reported, but the randomization method and a priori power analysis are not described.

Evidence

“Participants were randomized 6:2 to LY3475766 or placebo (0.9% sodium chloride) in each cohort.”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

“Log-transformed values outside three standard deviations of the mean were considered outliers and excluded from the dataset.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The study design is generally adequate for a phase 1 trial, but the randomization method is not described and a formal power analysis is absent, both of which are minor omissions for this early-phase study.

Evidence

“Participants were randomized 6:2 to LY3475766 or placebo (0.9% sodium chloride) in each cohort.”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

paraphrase[Methods, Study participants]

“Eligible participants were overtly healthy male or female adults 18–65 years of age, with a body mass index ≥18.5 to <40 kg m−2, fasting triglyceride level 135–499 mg dl−1, and fasting LDL-C level ≥70 mg dl−1.”

WARNReviewer 3· 85% conf

The study design is generally adequate for a phase 1 trial, but several design elements are underreported, such as the randomization method and blinding details, and no power analysis is provided.

Evidence

“Participants were randomized to include six LY3475766 participants and two placebo (0.9% sodium chloride) participants in each cohort”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

paraphrase[Methods, Study participants and Statistical analysis]

“Eligibility criteria and outlier exclusion (log-transformed values >3 SD) are described.”

The paper reports sex (36 men, 12 women) and age (median 49 years) and health status (overtly healthy) in the results and baseline table. However, race/ethnicity is not reported, which is a standard demographic variable. Since both sexes are enrolled, a justification for single-sex is not applicable. Species/strain and housing conditions are not applicable as this is a human trial.

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

Age, sex, BMI, and lipid-based health status are reported; race/ethnicity is not reported, and the trial enrolled both sexes so no single-sex justification is required.

Evidence

paraphrase[Results, Baseline characteristics]

“A total of 75% of the participants were male, with a median age of 49 years, body mass index of 30.4 kg m−2”

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia”

AbstractFind in source

PASSReviewer 2· 90% conf

Sex, age, and health status are reported, but race/ethnicity is not reported, which is a minor omission.

Evidence

paraphrase[Abstract, Table 1]

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia.”

paraphrase[Results, Baseline characteristics]

“A total of 75% of the participants were male, with a median age of 49 years, body mass index of 30.4 kg m−2, triglycerides 194 mg dl−1 and LDL-C 143 mg dl−1.”

absence[Table 1, Results]

Race/ethnicity is not reported in the baseline table or text.

PASSReviewer 3· 90% conf

Sex, age, weight, and health status are reported, and both sexes are included, but race/ethnicity is not reported.

Evidence

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia”

AbstractFind in source

paraphrase[Table 1 and Methods]

“Eligible participants were overtly healthy male or female adults 18–65 years of age, with a body mass index ≥18.5 to <40 kg m−2”

absence[Table 1 and Methods]

Race/ethnicity is not reported.

The paper states that the trial was approved by the institutional review board or ethics committee at each site, but does not name the specific board(s) or provide a protocol number in the approval statement (the protocol number J1T-MC-GZEA is given in the supplementary information). According to the guide, a named ethics body is required for adequacy. Informed consent is reported (written), and regulatory compliance with the Declaration of Helsinki and ICH GCP is stated. The missing IRB name does not indicate misconduct but is a reporting gap, resulting in a warn.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

IRB/ethics committee approval, written informed consent, and compliance with the Declaration of Helsinki and ICH-GCP are explicitly stated.

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

MethodsFind in source

“The trial was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, and applicable laws and regulations.”

MethodsFind in source

WARNReviewer 2· 90% conf

Ethics approval is stated but the specific IRB is not named; informed consent and regulatory compliance are adequately reported.

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

MethodsFind in source

WARNReviewer 3· 85% conf

The ethics statement is vague, not naming the specific IRB or protocol number, and although informed consent and regulatory compliance are reported, the missing details for the approval statement warrant a warning.

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

MethodsFind in source

The investigational product LY3475766 is identified with manufacturer (Eli Lilly), dose, and route. The placebo is 0.9% sodium chloride. Software tools are identified: Phoenix WinNonlin version 8.1 and SAS version 9.4. No bench reagents, antibodies, cell lines, or organisms were used in this clinical trial, so those sub-criteria are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

The investigational product (LY3475766) and analysis software are identified; bench-science resource criteria are not applicable to this clinical trial.

Evidence

“participants were given LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously”

MethodsFind in source

“Data analysis was performed using SAS version 9.4.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The investigational drug and software tools are adequately identified; bench reagents are not applicable.

Evidence

“LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously.”

MethodsFind in source

paraphrase[Methods, Pharmacokinetics and Statistical analysis]

“Pharmacokinetics were determined using noncompartmental methods (Phoenix WinNonlin version 8.1)... Data analysis was performed using SAS version 9.4.”

PASSReviewer 3· 90% conf

The investigational drug LY3475766 is adequately identified with dose and regimen, and statistical software is named with versions, meeting the applicable criteria.

Evidence

“participants were given LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously.”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

“Pharmacokinetics were determined using noncompartmental methods (Phoenix WinNonlin version 8.1)... Data analysis was performed using SAS version 9.4.”

The mixed model for repeated measures and Pearson correlation are named. Assumptions are not explicitly tested but the mixed model is a standard robust method. For the main efficacy outcomes, p-values are not reported; the paper reports least-squares mean differences with standard errors. Exact p-values are reported for the correlation analyses. Confidence intervals are only reported for the dose proportionality analysis. The statistical software SAS and Phoenix WinNonlin are identified. Data presentation includes per-group n, error bars (SE), and a participant flow diagram, which is adequate for a clinical trial. Mathematical plausibility is not applicable as the data are continuous and model-derived.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciNOT REPORTED

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 75% conf

Statistical tests and software are named, exact p-values are reported in correlation tables, and the estimation idiom (LS mean s.e.) is used for efficacy; effect sizes for the main lipid outcomes lack confidence intervals.

Evidence

“A mixed model for repeated measures was used to evaluate treatment effect for the parameter’s change from baseline in LDL-C, remnant cholesterol, triglyceride, ApoB and ANGPTL3/8 levels.”

Statistical analysisFind in source

“The ratio of the dose-normalized geometric mean C max of 600 mg versus 100 mg LY3475766 was 6.9 (90% confidence interval: 2.9–16.3).”

ResultsFind in source

“Figure shows the maximum least-squares mean (s.e.) percent placebo-adjusted changes observed after treatment with LY3475766 for triglycerides (−69.9% (4.7%))”

ResultsFind in source

PASSReviewer 2· 85% conf

Statistical tests are named, software is identified, and data presentation is adequate for a clinical trial, but exact p-values and confidence intervals are not reported for the primary efficacy comparisons.

Evidence

paraphrase[Methods, Statistical analysis]

“A mixed model for repeated measures was used to evaluate treatment effect... Pearson correlation analysis was conducted... Log-transformed Cmax estimates were evaluated using a power model.”

paraphrase[Methods, Statistical analysis; Results, Lipid profile correlation analysis]

“Due to computational limitations in SAS, P values are presented in the table to only four decimal places. Extended Data Tables 3–5 list Pearson correlation coefficients (r) and P values.”

“Data in the figure are given as the least-squares mean difference from placebo (s.e.).”

Figure 2Find in source

PASSReviewer 3· 80% conf

Statistical tests are named, exact p-values are reported in correlation tables, effect sizes with CIs are provided, and software is identified. However, assumption verification is incomplete and individual data points are not shown.

Evidence

paraphrase[Methods, Statistical analysis]

“A mixed model for repeated measures was used to evaluate treatment effect... Pearson correlation analysis was conducted to measure the correlation of changes from baseline at day 15 between two biomarkers.”

paraphrase[Results, Figure 2 and text]

“Figure shows the maximum least-squares mean (s.e.) percent placebo-adjusted changes... triglycerides (−69.9% (4.7%)), remnant cholesterol (−84.4% (10.2%))”

“The parameters were log-transformed prior to the analysis due to the skewness of the data.”

Statistical analysisFind in source

The data availability statement provides a concrete route: individual participant data are available via a managed-access platform (Vivli) after proposal approval, with conditions and timeframe specified. This is adequate for patient-level data. No custom code is shared, though the statistical analysis plan is provided in supplementary materials. The paper does not mention sharing analysis code, which is a common expectation for reproducibility.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

A detailed, concrete managed-access data-sharing statement is provided via the Vivli platform with defined conditions and timeframe.

Evidence

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data.”

Data availabilityFind in source

“For details on submitting a request, see the instructions provided at www.vivli.org”

Data availabilityFind in source

WARNReviewer 2· 90% conf

A detailed data availability statement with a concrete mechanism (Vivli) is provided, but custom code is not shared, which is a minor shortcoming.

Evidence

paraphrase[Data availability section]

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization... Data are available by request 6 months after the indication studied has been approved... For details on submitting a request, see the instructions provided at www.vivli.org.”

absence[Data availability section, Methods]

Custom code is not shared.

WARNReviewer 3· 90% conf

A data availability statement with a concrete access mechanism (Vivli) is provided, but custom analysis code is not shared, leading to a warning.

Evidence

paraphrase[Data availability section]

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization... For details on submitting a request, see the instructions provided at www.vivli.org”

absence[Data availability section]

No statement about sharing analysis code is present.

The methods section includes detailed trial design, participant selection, endpoints, assays, and statistical analysis. The trial is registered at ClinicalTrials.gov (NCT04052594). A reporting summary is linked. All pre-specified outcomes (safety, PK, PD) are reported, including negative results (no ADAs, no changes in some apolipoproteins). Limitations are discussed (e.g., single dose, need for further studies). Conclusions are measured and do not overclaim. Funding is from Eli Lilly, and competing interests are fully disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Trial registration, reporting summary, complete outcome reporting, limitations, proportional conclusions, and funding/COI disclosures are all present.

Evidence

“ClinicalTrials.gov registration: NCT04052594”

AbstractFind in source

“however, the effects on cardiovascular risk remain to be established.”

AbstractFind in source

“This work was supported by Eli Lilly and Company.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Methods are complete, the trial is registered, reporting guidelines are referenced, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

paraphrase[Abstract, Methods]

“ClinicalTrials.gov registration: NCT04052594.”

paraphrase[Discussion, last paragraph]

“The effects on cardiovascular risk remain to be established... Further studies are needed to confirm these findings...”

paraphrase[Acknowledgements, Competing interests]

“This work was supported by Eli Lilly and Company. D.G. reports consulting fees from... M.G., X.S., J.K.L., T.P.B., J.W.D., G.R.M., E.Y.Z., M.H., R.J.K., O.B. and G.R. are employees and shareholders of Eli Lilly and Company.”

PASSReviewer 3· 95% conf

The manuscript is well-structured, includes a clinical trial registration, a reporting summary, and detailed methods, with proportional conclusions and transparent funding/COI statements.

Evidence

“ClinicalTrials.gov registration: NCT04052594”

AbstractFind in source

“Further information on research design is available in the linked to this article.”

AbstractFind in source

“These results warrant further human trials to assess the safety and efficacy of LY3475766 for the treatment of lipid disorders”

DiscussionFind in source

Registered (1 ID: 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 48 references by DOI: 0 verified — 48 no DOI (shown, not verified).

3 data/code links checked; 3 live.

Copyediting

13 minor

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

No major wording or formatting errors. 13 minor suggestions below.

13 copyedit issues flagged: mostly typo, clarity, punctuation.

Kaimen Rigor Action ItemsFinal pass before journal submission

This is a post-publication audit. The published work is methodologically sound for its phase 1 purpose, but the reporting gaps (randomization method, IRB name, code sharing, CIs for main outcomes) are deficiencies that a reader should weigh. These issues are not validity threats but merit a correction or clarification from the authors. No erratum is required for the core conclusions, but the transparency gaps could be addressed via a data note or supplementary update.

1.
HIGHethics
Name the specific institutional review board(s) that approved the study in the Methods section (Trial design and oversight), and include the protocol number (J1T-MC-GZEA) in the main text.
The current statement ‘approved by the institutional review board or ethics committee at each site’ lacks the named board, which is a standard requirement for adequate ethics reporting.
2.
HIGHreporting
Describe the randomization method (e.g., computer-generated random sequence, block size, stratification) in the Methods section (Trial design and oversight).
The paper states that participants were randomized but does not specify the method, which is a key design detail for assessing bias.
3.
HIGHreporting
Provide a sample size justification or explicitly note that the study is a phase 1 dose-escalation trial without formal power analysis in the Methods section.
The absence of any sample size rationale is a reporting gap, though common in early-phase trials; an explicit statement clarifies the design intent.
4.
HIGHstatistics
Report 95% confidence intervals for the main lipid efficacy outcomes (e.g., least-squares mean percent change) in the Results or Figure 2.
Reporting only standard errors without confidence intervals limits the interpretability of effect sizes and is a common expectation for transparent reporting.
5.
HIGHdata code
Share the custom SAS analysis code used for the mixed model and correlation analyses via a public repository (e.g., GitHub or Zenodo) and cite it in the Data availability section.
The absence of analysis code limits reproducibility, especially for model-derived estimates. The data are available via Vivli, but code is not shared.
6.
HIGHreporting
Report race/ethnicity of participants in the baseline characteristics table (Table 1).
Race/ethnicity is a standard demographic variable; its omission is a minor but notable reporting gap in a clinical trial.
7.
MEDIUMreporting
Clarify the blinding procedure: specify who was blinded (participants, investigators, outcome assessors) and how blinding was maintained in the Methods section.
The paper only states ‘double-blind’ without details; this is insufficient for reproducibility and bias assessment.
8.
MEDIUMcopyedit
Correct the typo ‘ANPTL3/8’ to ‘ANGPTL3/8’ in the Abstract and throughout the text where it appears.
The misspelling of the target protein name is a copyedit error that should be corrected for clarity.
9.
MEDIUMcopyedit
Change ‘area under the operating curve’ to ‘area under the concentration-time curve (AUC)’ in the Results section (Pharmacokinetics and target engagement).
The term ‘operating curve’ is a typo for the correct pharmacokinetic term ‘concentration-time curve’.
10.
MEDIUMcopyedit
Fix the misplaced percentage sign in ‘−52.1 (6.3%)’ to ‘−52.1% (6.3%)’ in the Results section (Effects on triglyceride-rich lipoproteins).
The percentage sign should be on the point estimate, not the standard error, to avoid confusion.
11.
MEDIUMcopyedit
Revise the Table 1 title from ‘Baseline characteristics of healthy participants with dyslipidemia’ to ‘Baseline characteristics of participants with mixed hyperlipidemia’ to accurately describe the study population.
Labeling participants as ‘healthy’ while they have dyslipidemia is inconsistent with the disease definition and the abstract’s terminology.
12.
LOWreporting
Consider showing individual data points in the figures for the main outcomes (e.g., scatter plots) to improve data transparency, given the small sample sizes.
Individual data points would allow readers to assess variability and potential outliers beyond the summary statistics.
13.
LOWreporting
Include a description of the handling of missing data (e.g., due to COVID-19 disruption) in the Statistical analysis section.
The restart of the 300 mg cohort is described, but missing data handling is not explicitly addressed, which is relevant for the mixed model analysis.

Full text (52,716 chars)Analyzed: Aug 10, 2026

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Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial

Gaudet D, Gonciarz M, Shen X, Leohr JK, Beyer TP, Day JW, Mullins GR, Zhen EY, Hartley M, Larouche M, Konrad RJ, Benichou O, Ruotolo G.

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DOI

10.1038/s41591-025-03830-4

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Record fingerprint

5d918335ee1e27b4f852b40024240f51dbd70434294a440e6b278f3aaa80a29a

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Issued Aug 10, 2026Engine 7.29.0

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

Kaimen Rigor review

Kaimen Rigor reviewed

3.5 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ReportingEthical approvals partially met−0.25★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: moderateEngine: 7.29.0Source: full text

Not verified in this report

References were found (48) but none could be checked — every lookup failed or lacked a DOI.
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.

Findings by category

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Overstated conclusions

1 finding · worst low

Conclusions only partially backed by the presented evidenceAssessed

10 major claims checked against the paper's own evidence: all adequately supported.

Data authenticity concerns

1 finding · worst low

Other integrity concernAssessed

2 integrity concerns flagged (0 high).

Reporting gaps

2 findings · worst medium

Data/code availability incompleteAssessed
Ethics/consent reporting incompleteAssessed

Eight Dimensions6 pass · 2 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific foundation linking the ANGPTL3/8 complex to LPL inhibition and dyslipidemia, and justifies the target and the antibody.

Evidence

“Recent studies on how the ANGPTL protein family modulates LPL activity have identified the mechanisms by which LPL activity is controlled in a tissue-specific manner”

Introduction ¶1Find in source

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target.”

Introduction ¶5Find in source

Discussion ¶5Find in source

PASSReviewer 2· 95% conf

The paper establishes a strong scientific foundation by citing extensive prior work on ANGPTL3/8 and LPL, clearly rationalizing the study, and addressing limitations of previous approaches.

Evidence

paraphrase[Introduction, paragraphs 1-5]

paraphrase[Introduction, paragraph 5]

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target. Therefore, we developed a fully human anti-ANGPTL3/8 antibody, LY3475766...”

paraphrase[Discussion, paragraph 4]

PASSReviewer 3· 95% conf

Evidence

Main text, paragraphs 1-5Find in source

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target.”

Main text, paragraph 5Find in source

“The effects of ANGPTL3/8 inhibition on HDL metabolism were different from those of ANGPTL3 inhibition (as well as ANGPTL3 LOF mutations), in which a net decrease in HDL-C has been observed”

Discussion ¶4Find in source

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodNOT REPORTED

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 75% conf

Evidence

“Participants were randomized 6:2 to LY3475766 or placebo (0.9% sodium chloride) in each cohort.”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

“Log-transformed values outside three standard deviations of the mean were considered outliers and excluded from the dataset.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

Evidence

“Participants were randomized 6:2 to LY3475766 or placebo (0.9% sodium chloride) in each cohort.”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

paraphrase[Methods, Study participants]

WARNReviewer 3· 85% conf

The study design is generally adequate for a phase 1 trial, but several design elements are underreported, such as the randomization method and blinding details, and no power analysis is provided.

Evidence

“Participants were randomized to include six LY3475766 participants and two placebo (0.9% sodium chloride) participants in each cohort”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

paraphrase[Methods, Study participants and Statistical analysis]

“Eligibility criteria and outlier exclusion (log-transformed values >3 SD) are described.”

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

Age, sex, BMI, and lipid-based health status are reported; race/ethnicity is not reported, and the trial enrolled both sexes so no single-sex justification is required.

Evidence

paraphrase[Results, Baseline characteristics]

“A total of 75% of the participants were male, with a median age of 49 years, body mass index of 30.4 kg m−2”

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia”

AbstractFind in source

PASSReviewer 2· 90% conf

Sex, age, and health status are reported, but race/ethnicity is not reported, which is a minor omission.

Evidence

paraphrase[Abstract, Table 1]

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia.”

paraphrase[Results, Baseline characteristics]

“A total of 75% of the participants were male, with a median age of 49 years, body mass index of 30.4 kg m−2, triglycerides 194 mg dl−1 and LDL-C 143 mg dl−1.”

absence[Table 1, Results]

Race/ethnicity is not reported in the baseline table or text.

PASSReviewer 3· 90% conf

Sex, age, weight, and health status are reported, and both sexes are included, but race/ethnicity is not reported.

Evidence

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia”

AbstractFind in source

paraphrase[Table 1 and Methods]

“Eligible participants were overtly healthy male or female adults 18–65 years of age, with a body mass index ≥18.5 to <40 kg m−2”

absence[Table 1 and Methods]

Race/ethnicity is not reported.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

IRB/ethics committee approval, written informed consent, and compliance with the Declaration of Helsinki and ICH-GCP are explicitly stated.

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

MethodsFind in source

WARNReviewer 2· 90% conf

Ethics approval is stated but the specific IRB is not named; informed consent and regulatory compliance are adequately reported.

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

MethodsFind in source

WARNReviewer 3· 85% conf

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

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 (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

The investigational product (LY3475766) and analysis software are identified; bench-science resource criteria are not applicable to this clinical trial.

Evidence

“participants were given LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously”

MethodsFind in source

“Data analysis was performed using SAS version 9.4.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The investigational drug and software tools are adequately identified; bench reagents are not applicable.

Evidence

“LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously.”

MethodsFind in source

paraphrase[Methods, Pharmacokinetics and Statistical analysis]

“Pharmacokinetics were determined using noncompartmental methods (Phoenix WinNonlin version 8.1)... Data analysis was performed using SAS version 9.4.”

PASSReviewer 3· 90% conf

The investigational drug LY3475766 is adequately identified with dose and regimen, and statistical software is named with versions, meeting the applicable criteria.

Evidence

“participants were given LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously.”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

“Pharmacokinetics were determined using noncompartmental methods (Phoenix WinNonlin version 8.1)... Data analysis was performed using SAS version 9.4.”

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciNOT REPORTED

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 75% conf

Evidence

“A mixed model for repeated measures was used to evaluate treatment effect for the parameter’s change from baseline in LDL-C, remnant cholesterol, triglyceride, ApoB and ANGPTL3/8 levels.”

Statistical analysisFind in source

“The ratio of the dose-normalized geometric mean C max of 600 mg versus 100 mg LY3475766 was 6.9 (90% confidence interval: 2.9–16.3).”

ResultsFind in source

“Figure shows the maximum least-squares mean (s.e.) percent placebo-adjusted changes observed after treatment with LY3475766 for triglycerides (−69.9% (4.7%))”

ResultsFind in source

PASSReviewer 2· 85% conf

Evidence

paraphrase[Methods, Statistical analysis]

“A mixed model for repeated measures was used to evaluate treatment effect... Pearson correlation analysis was conducted... Log-transformed Cmax estimates were evaluated using a power model.”

paraphrase[Methods, Statistical analysis; Results, Lipid profile correlation analysis]

“Due to computational limitations in SAS, P values are presented in the table to only four decimal places. Extended Data Tables 3–5 list Pearson correlation coefficients (r) and P values.”

“Data in the figure are given as the least-squares mean difference from placebo (s.e.).”

Figure 2Find in source

PASSReviewer 3· 80% conf

Evidence

paraphrase[Methods, Statistical analysis]

paraphrase[Results, Figure 2 and text]

“Figure shows the maximum least-squares mean (s.e.) percent placebo-adjusted changes... triglycerides (−69.9% (4.7%)), remnant cholesterol (−84.4% (10.2%))”

“The parameters were log-transformed prior to the analysis due to the skewness of the data.”

Statistical analysisFind in source

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

A detailed, concrete managed-access data-sharing statement is provided via the Vivli platform with defined conditions and timeframe.

Evidence

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data.”

Data availabilityFind in source

“For details on submitting a request, see the instructions provided at www.vivli.org”

Data availabilityFind in source

WARNReviewer 2· 90% conf

A detailed data availability statement with a concrete mechanism (Vivli) is provided, but custom code is not shared, which is a minor shortcoming.

Evidence

paraphrase[Data availability section]

absence[Data availability section, Methods]

Custom code is not shared.

WARNReviewer 3· 90% conf

A data availability statement with a concrete access mechanism (Vivli) is provided, but custom analysis code is not shared, leading to a warning.

Evidence

paraphrase[Data availability section]

absence[Data availability section]

No statement about sharing analysis code is present.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Trial registration, reporting summary, complete outcome reporting, limitations, proportional conclusions, and funding/COI disclosures are all present.

Evidence

“ClinicalTrials.gov registration: NCT04052594”

AbstractFind in source

“however, the effects on cardiovascular risk remain to be established.”

AbstractFind in source

“This work was supported by Eli Lilly and Company.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Methods are complete, the trial is registered, reporting guidelines are referenced, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

paraphrase[Abstract, Methods]

“ClinicalTrials.gov registration: NCT04052594.”

paraphrase[Discussion, last paragraph]

“The effects on cardiovascular risk remain to be established... Further studies are needed to confirm these findings...”

paraphrase[Acknowledgements, Competing interests]

PASSReviewer 3· 95% conf

The manuscript is well-structured, includes a clinical trial registration, a reporting summary, and detailed methods, with proportional conclusions and transparent funding/COI statements.

Evidence

“ClinicalTrials.gov registration: NCT04052594”

AbstractFind in source

“Further information on research design is available in the linked to this article.”

AbstractFind in source

“These results warrant further human trials to assess the safety and efficacy of LY3475766 for the treatment of lipid disorders”

DiscussionFind in source

Registered (1 ID: 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 48 references by DOI: 0 verified — 48 no DOI (shown, not verified).

3 data/code links checked; 3 live.

Copyediting

13 minor

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

No major wording or formatting errors. 13 minor suggestions below.

13 copyedit issues flagged: mostly typo, clarity, punctuation.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHethics
Name the specific institutional review board(s) that approved the study in the Methods section (Trial design and oversight), and include the protocol number (J1T-MC-GZEA) in the main text.
The current statement ‘approved by the institutional review board or ethics committee at each site’ lacks the named board, which is a standard requirement for adequate ethics reporting.
2.
HIGHreporting
Describe the randomization method (e.g., computer-generated random sequence, block size, stratification) in the Methods section (Trial design and oversight).
The paper states that participants were randomized but does not specify the method, which is a key design detail for assessing bias.
3.
HIGHreporting
Provide a sample size justification or explicitly note that the study is a phase 1 dose-escalation trial without formal power analysis in the Methods section.
The absence of any sample size rationale is a reporting gap, though common in early-phase trials; an explicit statement clarifies the design intent.
4.
HIGHstatistics
Report 95% confidence intervals for the main lipid efficacy outcomes (e.g., least-squares mean percent change) in the Results or Figure 2.
Reporting only standard errors without confidence intervals limits the interpretability of effect sizes and is a common expectation for transparent reporting.
5.
HIGHdata code
Share the custom SAS analysis code used for the mixed model and correlation analyses via a public repository (e.g., GitHub or Zenodo) and cite it in the Data availability section.
The absence of analysis code limits reproducibility, especially for model-derived estimates. The data are available via Vivli, but code is not shared.
6.
HIGHreporting
Report race/ethnicity of participants in the baseline characteristics table (Table 1).
Race/ethnicity is a standard demographic variable; its omission is a minor but notable reporting gap in a clinical trial.
7.
MEDIUMreporting
Clarify the blinding procedure: specify who was blinded (participants, investigators, outcome assessors) and how blinding was maintained in the Methods section.
The paper only states ‘double-blind’ without details; this is insufficient for reproducibility and bias assessment.
8.
MEDIUMcopyedit
Correct the typo ‘ANPTL3/8’ to ‘ANGPTL3/8’ in the Abstract and throughout the text where it appears.
The misspelling of the target protein name is a copyedit error that should be corrected for clarity.
9.
MEDIUMcopyedit
Change ‘area under the operating curve’ to ‘area under the concentration-time curve (AUC)’ in the Results section (Pharmacokinetics and target engagement).
The term ‘operating curve’ is a typo for the correct pharmacokinetic term ‘concentration-time curve’.
10.
MEDIUMcopyedit
Fix the misplaced percentage sign in ‘−52.1 (6.3%)’ to ‘−52.1% (6.3%)’ in the Results section (Effects on triglyceride-rich lipoproteins).
The percentage sign should be on the point estimate, not the standard error, to avoid confusion.
11.
MEDIUMcopyedit
Revise the Table 1 title from ‘Baseline characteristics of healthy participants with dyslipidemia’ to ‘Baseline characteristics of participants with mixed hyperlipidemia’ to accurately describe the study population.
Labeling participants as ‘healthy’ while they have dyslipidemia is inconsistent with the disease definition and the abstract’s terminology.
12.
LOWreporting
Consider showing individual data points in the figures for the main outcomes (e.g., scatter plots) to improve data transparency, given the small sample sizes.
Individual data points would allow readers to assess variability and potential outliers beyond the summary statistics.
13.
LOWreporting
Include a description of the handling of missing data (e.g., due to COVID-19 disruption) in the Statistical analysis section.
The restart of the 300 mg cohort is described, but missing data handling is not explicitly addressed, which is relevant for the mixed model analysis.

Full text (52,716 chars)Analyzed: Aug 10, 2026