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
- DOI
- 10.1038/s41591-026-04313-w
- Record issued
- 2026-08-10
- Engine
- 7.29.0
- Exported
- 2026-09-21
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/9b9d1fa0-a2b3-40c6-ba99-c398453ef3b4 is authoritative.
How this rating was calculated
- ReportingStudy design partially met−0.25★
- ReportingEthical approvals partially met−0.25★
- ReportingKey resources partially met−0.25★
- Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.
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 foundValues 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 lowConclusions 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.
- partialReviewers 1, 2, 3XXB750 may paradoxically behave as a functional antagonist of endogenous natriuretic peptides in patients with heart failure.The evidence is consistent with antagonist behavior, but it is a hypothesis and not proven; the paper appropriately suggests this interpretation.Evidence: The opposite biomarker changes and worse clinical outcomes are consistent with antagonism, but alternative explanations are not ruled out.
“suggesting that XXB750 may paradoxically behave as a functional antagonist of endogenous natriuretic peptides in patients with heart failure.”
DiscussionFind in source - partialReviewer 3The adverse effects of XXB750 are more pronounced in patients on background sacubitril/valsartan than on ACEi or ARB.The subgroup analysis in Table 3 supports this direction, but the paper itself cautions that the early termination limited power to test interactions and this finding should be viewed with caution.Evidence: Table 3 shows greater NT-proBNP rise and cGMP fall and more worsening HF events in the sac/val background subgroups versus ACEi/ARB background.
“the finding that the adverse effects of XXB750 appear to be more pronounced in those patients on background sacubitril/valsartan needs to be viewed with caution”
DiscussionFind in source - supportedReviewers 1, 2, 3XXB750 treatment led to increased NT-proBNP levels, lowered cGMP levels and more worsening heart failure events.The evidence in Table 2 and Figure 2 shows the biomarker changes and adverse event rates support this claim.Evidence: Table 2 shows NT-proBNP ratio change 1.34 (1.07-1.66) and cGMP ratio change 0.77 (0.65-0.91) for pooled XXB750; worsening HF events 23.5% vs 0% in placebo.
“At 16 weeks, 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”
AbstractFind in source - supportedReviewer 1The increase in NT-proBNP and the reduction in cGMP with XXB750 were most apparent in those receiving background sacubitril/valsartan.Table 3 shows the biomarker changes are more pronounced in the background sac/val subgroup.Evidence: Table 3: For XXB750 120mg, NT-proBNP ratio change on background ACE/ARB: 1.21 (0.75-1.95) vs on background sac/val: 1.65 (1.16-2.33); cGMP ratio change: 0.98 (0.72-1.32) vs 0.64 (0.47-0.86).
“The increase in NT-proBNP and the reduction in cGMP with XXB750 were most apparent in those receiving background sacubitril/valsartan, with less meaningful changes observed in those receiving background ACEi or ARB”
Table 3Find in source - supportedReviewer 1The trial was terminated early due to evidence of harm in patients receiving XXB750.The DSMB recommendation and the reported adverse event rates support this claim.Evidence: The paper states the DSMB recommended termination due to excess worsening HF events.
“The trial was stopped following a recommendation of the data safety monitoring board on 6 August 2024 because of evidence of harm in patients receiving XXB750.”
AbstractFind in source - supportedReviewer 2The adverse effects of XXB750 are more pronounced in patients on background sacubitril/valsartan.Table 3 shows larger NT-proBNP increases and cGMP decreases in the background sacubitril/valsartan group compared to ACEi/ARB group. The paper notes caution due to small numbers.Evidence: Table 3, Discussion text
“those with the greatest tonic elevation of natriuretic peptides appeared to exhibit the greatest paradoxical effects of XXB750.”
Table 3Find in source - supportedReviewer 2These findings have implications for the development of natriuretic peptide therapeutics broadly beyond the current trial.The conclusion is reasonable based on the unexpected results, and the paper discusses implications for other agonists and alternative approaches.Evidence: Discussion
“These findings have implications for the development of natriuretic peptide therapeutics broadly beyond the current trial.”
DiscussionFind in source - supportedReviewer 3Worsening heart failure events occurred more frequently in XXB750 recipients than in sacubitril/valsartan or placebo recipients.Event counts in Table 2 (0%, 8%, and 24.7% for placebo, sac/val, and pooled XXB750) and the Kaplan-Meier curve directly support this claim.Evidence: Table 2: death or worsening HF event 0 (0.0%) placebo, 2 (8.0%) sac/val, 20 (24.7%) pooled XXB750.
“Death or worsening heart failure events occurred more frequently in those receiving XXB750 (25%) compared with those receiving sacubitril/valsartan (8%), or placebo (0%).”
AbstractFind in source - supportedReviewer 3The trial was terminated early on the recommendation of the data monitoring committee because of an excess of worsening heart failure events in XXB750 recipients.The methods and results directly document the DMC review on 6 August 2024 and its recommendation to terminate due to excess worsening HF events.Evidence: Methods > Data safety monitoring board and study termination describes the DMC recommendation; Results notes the trial was stopped.
“identified a marked increase in the frequency of worsening HF events in participants receiving XXB750 versus those on placebo or on sacubitril/valsartan and recommended the termination of the trial”
MethodsFind in source
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
3 findings · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Ethics/consent reporting incompleteAssessed
- Key resources under-identified (antibodies, cell lines, RRIDs)Assessed
- Study-design details incomplete (controls, blinding, power)Assessed
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.
“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.”
“Sustained stimulation of the NPR1 receptor offers a potential alternative approach to targeting the NP system.”
“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.”
“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.”
“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”
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).
“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.”
“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.”
“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.”
“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.”
“One patient in the 120 mg XXB750 group was misrandomized and was excluded from further analyses.”
“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%”
“Randomization was stratified by region and ACEi or ARB versus sacubitril/valsartan background therapy”
“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”
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.
“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).”
“We randomized 136 participants (70% male, 30% female)”
“The mean age was 69.8 years, with a range from 38 to 91 years, and 70% were men.”
“The individuals in the trial were predominantly white (84%), with most participants from Europe or the USA.”
“We randomized 136 participants (70% male, 30% female)”
“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%)”
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.
“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”
“Written informed consent was obtained from each patient.”
“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”
“Written informed consent was obtained from each patient.”
“The trial protocol (available with the full text of this article) was approved by institutional review boards or ethics committees at each trial center.”
“Written informed consent was obtained from each patient.”
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.
“participants randomized to open-label sacubitril/valsartan were titrated, where possible, to a target dose of 97/103 mg twice daily for 16 weeks.”
“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”
“participants randomized to open-label sacubitril/valsartan were titrated, where possible, to a target dose of 97/103 mg twice daily for 16 weeks.”
“XXB750, a long-acting fully human monoclonal IgG1 antibody targeting the NPR1 receptor”
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.
“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”
“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.”
“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”
“NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval (CI) 1.07–1.66)”
“log-rank P = 0.0038, comparing pooled XXB750 arms to the placebo arm.”
“increased in the pooled XXB750 arms (ratio change of 1.34, 95% CI 1.07–1.66)”
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.
“The data can be requested from https://www.novctrd.com/”
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.
“Clinicaltrials.gov registration: NCT06142383 (https://clinicaltrials.gov/study/NCT06142383) .”
“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.”
“The trial was funded by Novartis.”
“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.”
“The trial was funded by Novartis.”
“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.”
“The trial was funded by Novartis.”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences 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.
Every extracted reference resolved against Crossref/OpenAlex with no retraction flags.
2 data/code links checked; 2 live.
- datahttps://www.novctrd.com/LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/study/NCT06142383LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly consistency, clarity, other.
- MINORconsistencyResults, paragraph 1“26–60 mg XXB750, 56–120 mg XXB750”→ Consider changing to '26 to 60 mg XXB750, 56 to 120 mg XXB750' for clarity.The en dash may be misinterpreted as a range of doses rather than patient counts.
- MINORclarityTable 1, column header“XXB750 60 mg | n = 26 | XXB750 120 mg | n = 55”→ No change needed, but ensure consistency with the text.The table is clear.
- MINORotherAbstract“Patients with heart failure and a left ventricular ejection fraction <50% were enrolled.”→ No change needed.Clear.
- MINORclarityCompeting interests (C.S.P.L.)“U ( Us2.ai (http://Us2.ai) )”→ Simplify to 'Us2.ai'Awkward parenthetical nesting.
- MINORconsistencyResults, paragraph 1“26–60 mg XXB750, 56–120 mg XXB750”→ Change to '26 to 60 mg XXB750, 56 to 120 mg XXB750'Em-dash used where 'to' is clearer; not an error.
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.HIGHrigorDescribe 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.HIGHrigorSpecify 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.HIGHstatisticsDefine 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.HIGHethicsAdd 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.HIGHstatisticsIdentify 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.MEDIUMstatisticsAdd a sentence on the handling of missing data and dropouts in Methods > Statistical analysis.Strengthens missing-data/outlier reporting beyond the misrandomized exclusion.
- 7.MEDIUMethicsName 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.MEDIUMcopyeditChange '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.MEDIUMcopyeditSimplify 'U ( Us2.ai (http://Us2.ai) )' to 'Us2.ai' in Competing interests.The awkward parenthetical nesting harms readability.
- 10.LOWdata codeConsider 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.LOWreportingReference 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.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
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