Kaimen Rigor reviewed

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The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.

Name: Kaimen Rigor review — The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.
Item: The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.
Rating: 59
Author: Alpha1

Solomon SD, McMurray JJV, Felker GM, Januzzi JL, Lam CSP, Voors AA, Claggett B, Nuehrenberg TG, Rizkala AR, Koch C, Zhu W, Lefkowitz MP

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Kaimen Rigor review — 4.25★ (Strong), 0 critical, 5 high issues for “The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.”

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

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The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.

Solomon SD, McMurray JJV, Felker GM, Januzzi JL, Lam CSP, Voors AA, Claggett B, Nuehrenberg TG, Rizkala AR, Koch C, Zhu W, Lefkowitz MP

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DOI

10.1038/s41591-026-04313-w

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.

Solomon SD, McMurray JJV, Felker GM, Januzzi JL, Lam CSP, Voors AA, Claggett B, Nuehrenberg TG, Rizkala AR, Koch C, Zhu W, Lefkowitz MP

Paper source

The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized 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

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ReportingStudy design partially met−0.25★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★

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

Not verified in this report

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

01ArithmeticNone found 102OverreachOverstated conclusions 03AuthenticityNone found 304DisclosureReporting gaps 05AvailabilityNone found 06Copyedit5 minor suggestions

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

The paper is a well-written, transparent phase 2 RCT with a strong scientific rationale, comprehensive participant-characteristics reporting, and appropriate hypothesis-generating framing after early termination for safety. The main weaknesses are reporting gaps: randomization method and blinding scope are incompletely described, the analysis population is not formally defined, statistical software is not identified, and no regulatory-compliance framework is stated.

Three independent reviewer runs on the full text were synthesized; reviewers agreed on 6 of 8 dimensions, with divergence on study design (pass vs warn) and data code availability (pass vs warn) resolved by weighing specific omissions. The machine statistics checker could not verify any reported tests (coverage 0), so reported statistics were not independently recomputed; the citation check found no retracted or missing references.

Numerical inconsistencies

None found

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.

Checked — nothing surfaced.

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

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

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

3 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.

Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed
Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions5 pass · 3 warn

The introduction cites prior work on natriuretic peptides, sacubitril/valsartan, and NPR1 agonists. It establishes a rationale for sustained NPR1 stimulation. The limitations of short-acting neprilysin inhibition and bradykinin risk are acknowledged, and the long half-life of XXB750 is presented as a potential advantage.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper adequately cites prior research, provides a logical rationale, and addresses limitations of prior approaches.

Evidence

“Natriuretic peptides, including A- and B-type natriuretic peptide (ANP and BNP), are upregulated in HF and, through their action on the natriuretic peptide receptor 1 (NPR1, also known as NPRA) and membrane-bound particulate guanylate cyclase, stimulate natriuresis, diuresis and vasodilation.”

Introduction ¶1Find in source

“Sustained stimulation of the NPR1 receptor offers a potential alternative approach to targeting the NP system.”

Introduction ¶4Find in source

paraphrase[Introduction, paragraph 3]

“However, sacubitril/valsartan is relatively short-acting, augments bradykinin (resulting in a slight risk for angioedema) and may be less effective in patients with altered natriuretic peptide secretion and processing.”

PASSReviewer 2· 95% conf

The paper clearly cites prior research on natriuretic peptides and NPR1, provides a logical rationale for the study, and addresses limitations of prior approaches.

Evidence

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 2]

“Although the direct infusion of short-acting natriuretic peptides has not improved outcomes in acute decompensated HF, indirect augmentation of endogenous natriuretic peptide activity by neprilysin inhibition has proven effective in chronic HF, as demonstrated by the use of sacubitril/valsartan.”

“Because of the potential for XXB750 as a therapeutic for HF, we sought to assess the safety and efficacy of XXB750 in three doses given in different dosing regimens compared with placebo in patients with HF and left ventricular ejection fraction (LVEF) <50% receiving standard therapy.”

Introduction ¶3Find in source

PASSReviewer 3· 85% conf

The scientific premise is well established with a thorough review of natriuretic peptide biology and prior therapeutic attempts, and a clear, logically-derived hypothesis.

Evidence

paraphrase[Introduction, paragraph 2-3]

“we sought to assess the safety and efficacy of XXB750 in three doses given in different dosing regimens compared with placebo in patients with HF”

IntroductionFind in source

The paper states 'randomized' but does not describe the method (e.g., computer-generated random numbers). Blinding is described as 'blinded' for XXB750 and placebo but without details on who was blinded or the blinding procedure. The power analysis is reported for the original planned sample size. Inclusion/exclusion criteria are clearly defined. The analysis population is not explicitly defined as ITT or per-protocol, and one misrandomized patient was excluded without a clear population definition. Controls are appropriate (placebo and sacubitril/valsartan).

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsINADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study design is adequately described, including randomization, blinding, power analysis, and inclusion/exclusion criteria, though outlier handling is not reported.

Evidence

“Randomization was stratified by region and ACEi or ARB versus sacubitril/valsartan background therapy to ensure that the XXB750 or placebo arms had approximately two thirds of patients on background sacubitril/valsartan therapy.”

MethodsFind in source

“Those patients who were on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment were randomized to receive 60 mg XXB750, 120 mg XXB750 or placebo in a blinded fashion or sacubitril/valsartan treatment in an open-label fashion.”

AbstractFind in source

paraphrase[Methods, Statistical analysis]

“Assuming a common standard deviation of 0.67 for log NT-proBNP change from baseline and a two-sided 5% significance level, a sample size of 600 participants... would have provided a power of 90% if the underlying true maximum NT-proBNP reduction with XXB750 versus placebo was 23%.”

WARNReviewer 2· 85% conf

The randomization method is not specified, blinding is incompletely described, and the analysis population is not fully defined, leading to a warning.

Evidence

“Individuals who met eligibility criteria who were on background ACEi or ARB were randomly allocated to receive blinded subcutaneous XXB750 60-mg doses, XXB750 titrated to a maximum dose of 120 mg, matching subcutaneous placebo or open-label oral sacubitril/valsartan.”

MethodsFind in source

AbstractFind in source

“One patient in the 120 mg XXB750 group was misrandomized and was excluded from further analyses.”

Results ¶1Find in source

WARNReviewer 3· 70% conf

Core design elements (power analysis, inclusion/exclusion, randomization stratification) are well reported, but the randomization method, full blinding scope, and analysis-population handling are incompletely described.

Evidence

“a sample size of 600 participants (120 allocated to placebo, 120 to 60 mg of XXB750, 180 to 120 mg of XXB750 and 180 to 240 mg of XXB750) would have provided a power of 90% if the underlying true maximum NT-proBNP reduction with XXB750 versus placebo was 23%”

Statistical analysisFind in source

“Randomization was stratified by region and ACEi or ARB versus sacubitril/valsartan background therapy”

MethodsFind in source

“were randomly allocated to receive blinded subcutaneous XXB750 60-mg doses, XXB750 titrated to a maximum dose of 120 mg, matching subcutaneous placebo or open-label oral sacubitril/valsartan”

MethodsFind in source

Sex is reported as 70% male, 30% female. Age is reported as mean 69.8 years. Health status is detailed with LVEF, eGFR, NT-proBNP, etc. Demographics include race, region, comorbidities in Table 1.

Sub-criteria

demographicsADEQUATE

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· 100% conf

Sex, age, BMI, health status, and demographics are well reported.

Evidence

“We randomized 136 participants (70% male, 30% female) to 60 mg XXB750 ( n = 26), 120 mg XXB750 ( n = 55), matching placebo ( n = 29) or sacubitril/valsartan ( n = 25).”

AbstractFind in source

paraphrase[Results, paragraph 1]

“The mean age was 69.8 years, with a range from 38 to 91 years, and 70% were men. The mean LVEF at baseline was 36.8% ± 8.1%. The mean estimated glomerular filtration rate (eGFR) was 66.3 ± 22 ml min 1.73 m − 2 , and the median NT-proBNP was 1391 ng l −1 (interquartile range 956–2,436).”

paraphrase[Table 1]

“Table 1 Baseline characteristics by randomized group ... Race: White 86.2% etc.”

PASSReviewer 2· 95% conf

Sex, age, health status, and demographics are adequately reported for the human participants.

Evidence

“We randomized 136 participants (70% male, 30% female)”

AbstractFind in source

“The mean age was 69.8 years, with a range from 38 to 91 years, and 70% were men.”

Results ¶1Find in source

“The individuals in the trial were predominantly white (84%), with most participants from Europe or the USA.”

Results ¶1Find in source

PASSReviewer 3· 90% conf

Sex, age, health status, and human demographics are comprehensively reported for the trial population.

Evidence

“We randomized 136 participants (70% male, 30% female)”

Table 1Find in source

“The mean age was 69.8 years, with a range from 38 to 91 years, and 70% were men. The majority of patients had a history of hypertension (88%)”

Results ¶1Find in source

The paper states that the protocol was approved by institutional review boards or ethics committees at each trial center, but does not name a specific committee. Written informed consent was obtained. No statement of compliance with Declaration of Helsinki or ICH-GCP is provided.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Informed consent is adequately reported, but the ethics approval statement does not name a specific IRB/ethics committee, and regulatory compliance with a recognized framework is not stated.

Evidence

“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”

MethodsFind in source

“Written informed consent was obtained from each patient.”

MethodsFind in source

absence[Methods]

Regulatory compliance not stated.

WARNReviewer 2· 85% conf

The ethics approval statement is generic and does not name the specific IRB, and regulatory compliance with a recognized framework is not stated.

Evidence

“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”

MethodsFind in source

“Written informed consent was obtained from each patient.”

MethodsFind in source

absence[Methods]

Regulatory compliance is not stated.

WARNReviewer 3· 75% conf

Ethics approval by IRB/ethics committees and written informed consent are documented, but no explicit regulatory-compliance statement (e.g., Declaration of Helsinki, ICH-GCP) is provided.

Evidence

“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”

MethodsFind in source

“Written informed consent was obtained from each patient.”

MethodsFind in source

absence[Whole manuscript]

No regulatory compliance statement found.

The drug XXB750 is described as a human monoclonal antibody, with doses and regimen provided. Sacubitril/valsartan is described with dose. No statistical software version is mentioned.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

The investigational product XXB750 and comparator sacubitril/valsartan are adequately described, but the statistical software used is not identified.

Evidence

paraphrase[Abstract, Methods]

“XXB750, a long-acting fully human monoclonal IgG1 antibody targeting the NPR1 receptor, has been shown to increase plasma cGMP in a dose-dependent fashion and correspondingly reduce blood pressure in healthy normotensive and hypertensive participants not taking antihypertensive medications.”

“participants randomized to open-label sacubitril/valsartan were titrated, where possible, to a target dose of 97/103 mg twice daily for 16 weeks.”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software not identified.

WARNReviewer 2· 85% conf

The investigational product is adequately identified, but the statistical software used for analysis is not reported.

Evidence

“XXB750, a long-acting fully human monoclonal IgG1 antibody targeting the NPR1 receptor, has been shown to increase plasma cGMP in a dose-dependent fashion”

AbstractFind in source

“participants randomized to open-label sacubitril/valsartan were titrated, where possible, to a target dose of 97/103 mg twice daily for 16 weeks.”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software is not identified.

WARNReviewer 3· 70% conf

The investigational product XXB750 and comparator are identified with doses and manufacturer, but the statistical analysis software is not identified.

Evidence

“XXB750, a long-acting fully human monoclonal IgG1 antibody targeting the NPR1 receptor”

IntroductionFind in source

absence[Methods, Statistical analysis]

Statistical software not identified.

The log-rank test and ANCOVA are named. Exact p-values are reported (P=0.0038, P interaction=0.70, 0.49). Ratio changes with 95% CIs are provided for all biomarkers. Data are presented in tables and violin plots. Statistical software is not mentioned.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Statistical tests are named, exact p-values are reported, effect sizes with confidence intervals are provided, and data presentation is adequate. Software is not identified, but this is a minor omission.

Evidence

“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”

Figure 3Find in source

paraphrase[Results, paragraph 1]

“NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval (CI) 1.07–1.66) and cyclic guanosine monophosphate (cGMP) levels declined (ratio of change from baseline 0.77, 95% CI 0.65–0.91) in the pooled XXB750 arms.”

paraphrase[Results, paragraph 2]

“We observed no heterogeneity in the response to XXB750 for either NT-proBNP ( P interaction of 0.70) or cGMP ( P interaction of 0.49) according to baseline NT-proBNP concentration.”

PASSReviewer 2· 90% conf

The paper reports effect sizes with 95% CIs, uses appropriate methods, and presents data adequately, though the statistical software is not named.

Evidence

“The primary endpoint of change in NT-proBNP was summarized descriptively as geometric means and 95% CI for each treatment group administered in the trial and by pooling the two XXB750 groups.”

Statistical analysisFind in source

“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”

Figure 3Find in source

“NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval (CI) 1.07–1.66)”

Results ¶1Find in source

PASSReviewer 3· 70% conf

Statistical tests are named, exact p-values and effect estimates with 95% CIs are reported, and data presentation follows the clinical-trial idiom; only the statistical software is not identified.

Evidence

“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”

Figure 3Find in source

“increased in the pooled XXB750 arms (ratio change of 1.34, 95% CI 1.07–1.66)”

ResultsFind in source

absence[Methods, Statistical analysis]

Statistical software not named.

The paper states that data are not publicly available but can be requested via https://www.novctrd.com/, describing the review process. This is adequate for a clinical trial with patient-level data.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 100% conf

A data availability statement is provided with a concrete access route via the Novartis data request portal.

Evidence

paraphrase[Data availability section]

“The data from this clinical trial are not publicly available. Novartis is committed to sharing access to patient-level data and supporting clinical documents with qualified external researchers. These requests are reviewed on an ongoing basis and approved expeditiously on the basis of scientific merit based on the policies described at the website below. All data provided are anonymized to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. The data can be requested from https://www.novctrd.com/.”

WARNReviewer 2· 90% conf

A data availability statement with a concrete access route is provided, but custom analysis code is not shared.

Evidence

paraphrase[Data availability section]

absence[Data availability section, Methods]

Code sharing is not mentioned.

PASSReviewer 3· 85% conf

A concrete data-access route via the Novartis data-sharing portal is provided; other criteria are not applicable to identifiable patient-level data.

Evidence

“The data can be requested from https://www.novctrd.com/”

Data availabilityFind in source

Methods are detailed with protocol available. Trial registration number is provided. A reporting summary is linked. All pre-specified outcomes are reported. Limitations are discussed. Conclusions are cautious. Funding 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· 100% conf

The paper is transparent: methods are complete, trial is registered, reporting guideline is referenced, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“Clinicaltrials.gov registration: NCT06142383 (https://clinicaltrials.gov/study/NCT06142383) .”

AbstractFind in source

“These findings need to be considered in light of their limitations. Because the trial was terminated early for safety concerns, it lacked sufficient power to adequately test the primary biomarker hypothesis, and the data presented need to be considered hypothesis-generating.”

Discussion ¶5Find in source

“The trial was funded by Novartis.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

The paper is well-reported with a registered trial, detailed methods, and transparent discussion of limitations and funding.

Evidence

paraphrase[Abstract, Methods]

“Clinicaltrials.gov registration: NCT06142383 (https://clinicaltrials.gov/study/NCT06142383).”

“Because the trial was terminated early for safety concerns, it lacked sufficient power to adequately test the primary biomarker hypothesis, and the data presented need to be considered hypothesis-generating.”

Discussion ¶5Find in source

“The trial was funded by Novartis.”

AcknowledgementsFind in source

PASSReviewer 3· 85% conf

The manuscript is transparent and complete: trial registration, detailed methods, full outcome reporting including negative results, limitations, and funding/COI are all present.

Evidence

“Clinicaltrials.gov registration: NCT06142383 (https://clinicaltrials.gov/study/NCT06142383)”

AbstractFind in source

DiscussionFind in source

“The trial was funded by Novartis.”

AcknowledgementsFind 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 23 references by DOI: 23 verified.

2 data/code links checked; 2 live.

Copyediting

5 minor

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

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

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

Kaimen Rigor Action ItemsFinal pass before journal submission

In this post-publication audit, the published work is generally robust and transparent, but informed readers should weigh the incomplete reporting of randomization method, blinding scope, and analysis population, plus the absent regulatory-compliance statement and statistical software identification. These are reporting gaps that would warrant a correction or supplementary clarification rather than invalidating the findings; the early termination and hypothesis-generating framing are appropriately disclosed.

1.
HIGHrigor
Describe the exact randomization allocation method (e.g., computer-generated sequence, block/permuted-block size) in Methods > Trial procedures.
The paper states 'randomized' and 'stratified' but not how the allocation sequence was generated, a standard CONSORT item required for reproducibility.
2.
HIGHrigor
Specify the blinding scope (who was blinded: patients, investigators, outcome assessors) and the design/rationale for the open-label sacubitril/valsartan arm in Methods > Trial design.
Blinding is described only as 'blinded fashion' without identifying all blinded parties, which is key to assessing bias.
3.
HIGHstatistics
Define the analysis population (full analysis set/intention-to-treat vs per-protocol) and state how the single misrandomized patient and missing data were handled in Methods > Statistical analysis.
The manuscript excludes a misrandomized patient without a formal population definition, which affects interpretation of all efficacy results.
4.
HIGHethics
Add an explicit regulatory-compliance statement (e.g., 'conducted in accordance with the Declaration of Helsinki and ICH-GCP') to Methods > Trial design and oversight.
All reviewers flagged the absence of a recognized ethics-compliance framework.
5.
HIGHstatistics
Identify the statistical software and version used for all analyses in Methods > Statistical analysis.
No software is named, which limits reproducibility and was flagged by all three reviewers.
6.
MEDIUMstatistics
Add a sentence on the handling of missing data and dropouts in Methods > Statistical analysis.
Strengthens missing-data/outlier reporting beyond the misrandomized exclusion.
7.
MEDIUMethics
Name the specific IRB/ethics committee(s) and protocol number in the ethics approval statement (or in the supplementary protocol).
Reviewers 1 and 2 flagged the generic 'approved by institutional review boards or ethics committees at each trial center' as insufficiently specific.
8.
MEDIUMcopyedit
Change '26–60 mg XXB750, 56–120 mg XXB750' to '26 to 60 mg XXB750, 56 to 120 mg XXB750' in Results, paragraph 1.
The en dash could be misread as a dose range rather than patient counts.
9.
MEDIUMcopyedit
Simplify 'U ( Us2.ai (http://Us2.ai) )' to 'Us2.ai' in Competing interests.
The awkward parenthetical nesting harms readability.
10.
LOWdata code
Consider sharing custom statistical analysis code in a public repository (e.g., GitHub/Zenodo) with a DOI, referenced in the Data availability section.
Optional for a clinical trial with managed-access data, but would improve analytic transparency.
11.
LOWreporting
Reference the specific reporting guideline (e.g., CONSORT 2010) alongside the Nature Portfolio reporting summary in Methods.
One reviewer noted no explicit guideline; formal citation would strengthen compliance evidence.

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The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.

Solomon SD, McMurray JJV, Felker GM, Januzzi JL, Lam CSP, Voors AA, Claggett B, Nuehrenberg TG, Rizkala AR, Koch C, Zhu W, Lefkowitz MP

Read full text (PMC)

DOI

10.1038/s41591-026-04313-w

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Record fingerprint

445f3061b792b97ae9a97d3d95e78e7a4dd9102f7980735566285da3a06acd65

Verify via API

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

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ReportingStudy design partially met−0.25★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★

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

Not verified in this report

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

01ArithmeticNone found 102OverreachOverstated conclusions 03AuthenticityNone found 304DisclosureReporting gaps 05AvailabilityNone found 06Copyedit5 minor suggestions

Numerical inconsistencies

None found

Checked — nothing surfaced.

Overstated conclusions

1 finding · worst low

Conclusions only partially backed by the presented evidenceAssessed

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

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

3 findings · worst medium

Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed
Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions5 pass · 3 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper adequately cites prior research, provides a logical rationale, and addresses limitations of prior approaches.

Evidence

Introduction ¶1Find in source

“Sustained stimulation of the NPR1 receptor offers a potential alternative approach to targeting the NP system.”

Introduction ¶4Find in source

paraphrase[Introduction, paragraph 3]

PASSReviewer 2· 95% conf

The paper clearly cites prior research on natriuretic peptides and NPR1, provides a logical rationale for the study, and addresses limitations of prior approaches.

Evidence

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 2]

Introduction ¶3Find in source

PASSReviewer 3· 85% conf

The scientific premise is well established with a thorough review of natriuretic peptide biology and prior therapeutic attempts, and a clear, logically-derived hypothesis.

Evidence

paraphrase[Introduction, paragraph 2-3]

“we sought to assess the safety and efficacy of XXB750 in three doses given in different dosing regimens compared with placebo in patients with HF”

IntroductionFind in source

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsINADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study design is adequately described, including randomization, blinding, power analysis, and inclusion/exclusion criteria, though outlier handling is not reported.

Evidence

MethodsFind in source

AbstractFind in source

paraphrase[Methods, Statistical analysis]

WARNReviewer 2· 85% conf

The randomization method is not specified, blinding is incompletely described, and the analysis population is not fully defined, leading to a warning.

Evidence

MethodsFind in source

AbstractFind in source

“One patient in the 120 mg XXB750 group was misrandomized and was excluded from further analyses.”

Results ¶1Find in source

WARNReviewer 3· 70% conf

Evidence

Statistical analysisFind in source

“Randomization was stratified by region and ACEi or ARB versus sacubitril/valsartan background therapy”

MethodsFind in source

“were randomly allocated to receive blinded subcutaneous XXB750 60-mg doses, XXB750 titrated to a maximum dose of 120 mg, matching subcutaneous placebo or open-label oral sacubitril/valsartan”

MethodsFind in source

Sex is reported as 70% male, 30% female. Age is reported as mean 69.8 years. Health status is detailed with LVEF, eGFR, NT-proBNP, etc. Demographics include race, region, comorbidities in Table 1.

Sub-criteria

demographicsADEQUATE

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· 100% conf

Sex, age, BMI, health status, and demographics are well reported.

Evidence

“We randomized 136 participants (70% male, 30% female) to 60 mg XXB750 ( n = 26), 120 mg XXB750 ( n = 55), matching placebo ( n = 29) or sacubitril/valsartan ( n = 25).”

AbstractFind in source

paraphrase[Results, paragraph 1]

paraphrase[Table 1]

“Table 1 Baseline characteristics by randomized group ... Race: White 86.2% etc.”

PASSReviewer 2· 95% conf

Sex, age, health status, and demographics are adequately reported for the human participants.

Evidence

“We randomized 136 participants (70% male, 30% female)”

AbstractFind in source

“The mean age was 69.8 years, with a range from 38 to 91 years, and 70% were men.”

Results ¶1Find in source

“The individuals in the trial were predominantly white (84%), with most participants from Europe or the USA.”

Results ¶1Find in source

PASSReviewer 3· 90% conf

Sex, age, health status, and human demographics are comprehensively reported for the trial population.

Evidence

“We randomized 136 participants (70% male, 30% female)”

Table 1Find in source

“The mean age was 69.8 years, with a range from 38 to 91 years, and 70% were men. The majority of patients had a history of hypertension (88%)”

Results ¶1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Informed consent is adequately reported, but the ethics approval statement does not name a specific IRB/ethics committee, and regulatory compliance with a recognized framework is not stated.

Evidence

“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”

MethodsFind in source

“Written informed consent was obtained from each patient.”

MethodsFind in source

absence[Methods]

Regulatory compliance not stated.

WARNReviewer 2· 85% conf

The ethics approval statement is generic and does not name the specific IRB, and regulatory compliance with a recognized framework is not stated.

Evidence

“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”

MethodsFind in source

“Written informed consent was obtained from each patient.”

MethodsFind in source

absence[Methods]

Regulatory compliance is not stated.

WARNReviewer 3· 75% conf

Ethics approval by IRB/ethics committees and written informed consent are documented, but no explicit regulatory-compliance statement (e.g., Declaration of Helsinki, ICH-GCP) is provided.

Evidence

“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”

MethodsFind in source

“Written informed consent was obtained from each patient.”

MethodsFind in source

absence[Whole manuscript]

No regulatory compliance statement found.

The drug XXB750 is described as a human monoclonal antibody, with doses and regimen provided. Sacubitril/valsartan is described with dose. No statistical software version is mentioned.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

The investigational product XXB750 and comparator sacubitril/valsartan are adequately described, but the statistical software used is not identified.

Evidence

paraphrase[Abstract, Methods]

“participants randomized to open-label sacubitril/valsartan were titrated, where possible, to a target dose of 97/103 mg twice daily for 16 weeks.”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software not identified.

WARNReviewer 2· 85% conf

The investigational product is adequately identified, but the statistical software used for analysis is not reported.

Evidence

“XXB750, a long-acting fully human monoclonal IgG1 antibody targeting the NPR1 receptor, has been shown to increase plasma cGMP in a dose-dependent fashion”

AbstractFind in source

“participants randomized to open-label sacubitril/valsartan were titrated, where possible, to a target dose of 97/103 mg twice daily for 16 weeks.”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software is not identified.

WARNReviewer 3· 70% conf

The investigational product XXB750 and comparator are identified with doses and manufacturer, but the statistical analysis software is not identified.

Evidence

“XXB750, a long-acting fully human monoclonal IgG1 antibody targeting the NPR1 receptor”

IntroductionFind in source

absence[Methods, Statistical analysis]

Statistical software not identified.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”

Figure 3Find in source

paraphrase[Results, paragraph 1]

paraphrase[Results, paragraph 2]

“We observed no heterogeneity in the response to XXB750 for either NT-proBNP ( P interaction of 0.70) or cGMP ( P interaction of 0.49) according to baseline NT-proBNP concentration.”

PASSReviewer 2· 90% conf

The paper reports effect sizes with 95% CIs, uses appropriate methods, and presents data adequately, though the statistical software is not named.

Evidence

“The primary endpoint of change in NT-proBNP was summarized descriptively as geometric means and 95% CI for each treatment group administered in the trial and by pooling the two XXB750 groups.”

Statistical analysisFind in source

“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”

Figure 3Find in source

“NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval (CI) 1.07–1.66)”

Results ¶1Find in source

PASSReviewer 3· 70% conf

Statistical tests are named, exact p-values and effect estimates with 95% CIs are reported, and data presentation follows the clinical-trial idiom; only the statistical software is not identified.

Evidence

“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”

Figure 3Find in source

“increased in the pooled XXB750 arms (ratio change of 1.34, 95% CI 1.07–1.66)”

ResultsFind in source

absence[Methods, Statistical analysis]

Statistical software not named.

The paper states that data are not publicly available but can be requested via https://www.novctrd.com/, describing the review process. This is adequate for a clinical trial with patient-level data.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 100% conf

A data availability statement is provided with a concrete access route via the Novartis data request portal.

Evidence

paraphrase[Data availability section]

WARNReviewer 2· 90% conf

A data availability statement with a concrete access route is provided, but custom analysis code is not shared.

Evidence

paraphrase[Data availability section]

absence[Data availability section, Methods]

Code sharing is not mentioned.

PASSReviewer 3· 85% conf

A concrete data-access route via the Novartis data-sharing portal is provided; other criteria are not applicable to identifiable patient-level data.

Evidence

“The data can be requested from https://www.novctrd.com/”

Data availabilityFind in source

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· 100% conf

Evidence

“Clinicaltrials.gov registration: NCT06142383 (https://clinicaltrials.gov/study/NCT06142383) .”

AbstractFind in source

Discussion ¶5Find in source

“The trial was funded by Novartis.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

The paper is well-reported with a registered trial, detailed methods, and transparent discussion of limitations and funding.

Evidence

paraphrase[Abstract, Methods]

“Clinicaltrials.gov registration: NCT06142383 (https://clinicaltrials.gov/study/NCT06142383).”

Discussion ¶5Find in source

“The trial was funded by Novartis.”

AcknowledgementsFind in source

PASSReviewer 3· 85% conf

The manuscript is transparent and complete: trial registration, detailed methods, full outcome reporting including negative results, limitations, and funding/COI are all present.

Evidence

“Clinicaltrials.gov registration: NCT06142383 (https://clinicaltrials.gov/study/NCT06142383)”

AbstractFind in source

DiscussionFind in source

“The trial was funded by Novartis.”

AcknowledgementsFind 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 23 references by DOI: 23 verified.

2 data/code links checked; 2 live.

Copyediting

5 minor

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

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

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHrigor
Describe the exact randomization allocation method (e.g., computer-generated sequence, block/permuted-block size) in Methods > Trial procedures.
The paper states 'randomized' and 'stratified' but not how the allocation sequence was generated, a standard CONSORT item required for reproducibility.
2.
HIGHrigor
Specify the blinding scope (who was blinded: patients, investigators, outcome assessors) and the design/rationale for the open-label sacubitril/valsartan arm in Methods > Trial design.
Blinding is described only as 'blinded fashion' without identifying all blinded parties, which is key to assessing bias.
3.
HIGHstatistics
Define the analysis population (full analysis set/intention-to-treat vs per-protocol) and state how the single misrandomized patient and missing data were handled in Methods > Statistical analysis.
The manuscript excludes a misrandomized patient without a formal population definition, which affects interpretation of all efficacy results.
4.
HIGHethics
Add an explicit regulatory-compliance statement (e.g., 'conducted in accordance with the Declaration of Helsinki and ICH-GCP') to Methods > Trial design and oversight.
All reviewers flagged the absence of a recognized ethics-compliance framework.
5.
HIGHstatistics
Identify the statistical software and version used for all analyses in Methods > Statistical analysis.
No software is named, which limits reproducibility and was flagged by all three reviewers.
6.
MEDIUMstatistics
Add a sentence on the handling of missing data and dropouts in Methods > Statistical analysis.
Strengthens missing-data/outlier reporting beyond the misrandomized exclusion.
7.
MEDIUMethics
Name the specific IRB/ethics committee(s) and protocol number in the ethics approval statement (or in the supplementary protocol).
Reviewers 1 and 2 flagged the generic 'approved by institutional review boards or ethics committees at each trial center' as insufficiently specific.
8.
MEDIUMcopyedit
Change '26–60 mg XXB750, 56–120 mg XXB750' to '26 to 60 mg XXB750, 56 to 120 mg XXB750' in Results, paragraph 1.
The en dash could be misread as a dose range rather than patient counts.
9.
MEDIUMcopyedit
Simplify 'U ( Us2.ai (http://Us2.ai) )' to 'Us2.ai' in Competing interests.
The awkward parenthetical nesting harms readability.
10.
LOWdata code
Consider sharing custom statistical analysis code in a public repository (e.g., GitHub/Zenodo) with a DOI, referenced in the Data availability section.
Optional for a clinical trial with managed-access data, but would improve analytic transparency.
11.
LOWreporting
Reference the specific reporting guideline (e.g., CONSORT 2010) alongside the Nature Portfolio reporting summary in Methods.
One reviewer noted no explicit guideline; formal citation would strengthen compliance evidence.

Full text (43,563 chars)Analyzed: Aug 10, 2026