Dear Dr. Nagano,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 31 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Ken Iseri

Academic Editor

PLOS One

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following in the Competing Interests section:

“Nobuo Nagano received consultancies from Kyowa Kirin Co., Ltd.; honoraria from Kyowa Kirin Co., Ltd.; Kissei Pharmaceutical Co., Ltd.; Toa Shinyaku Co., Ltd.; Nobelpharma Co., Ltd.; Torii Pharmaceutical Co.,Ltd.; and Ono Pharmaceutical Co., Ltd.

Shin Tokunaga and Shinji Asada are employees of Kyowa Kirin Co., Ltd.

Masafumi Fukagawa received grants from Kyowa Kirin Co., Ltd. to his institution; consulting fees and honoraria from Sanwa Kagaku Kenkyusho Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Kyowa Kirin Co., Ltd.; Bayer Yakuhin, Ltd.; Kissei Pharmaceutical Co., Ltd.; and Torii Pharmaceutical Co., Ltd.

Tadao Akizawa received consulting fees from Kyowa Kirin Co., Ltd.; Kissei Pharmaceutical Co., Ltd.; Torii Pharmaceutical Co., Ltd.; and Sanwa Kagaku Kenkyusho Co., Ltd.; honoraria from Kyowa Kirin Co., Ltd.; Kissei Pharmaceutical Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Torii Pharmaceutical Co., Ltd.; and Sanwa Kagaku Kenkyusho Co., Ltd.; support for travel fee from Kyowa Kirin Co., Ltd.”

We note that one or more of the authors are employed by a commercial company: Kyowa Kirin Co., Ltd.; Kissei Pharmaceutical Co., Ltd.; Toa Shinyaku Co., Ltd.; Nobelpharma Co., Ltd.; Torii Pharmaceutical Co.,Ltd.; and Ono Pharmaceutical Co., Ltd.  And Sanwa Kagaku Kenkyusho Co., Ltd.;

1. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

Please also include the following statement within your amended Funding Statement.

“The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

2. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.

Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests) . If this adherence statement is not accurate and  there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf.

4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

5. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Additional Editor Comments:

Please address reviewer's comments.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

Reviewer #1: The team pooled data from three trials to characterize the sample associated with the need for higher tenapanor doses. The results showed that the serum TRACP-5b and BSFS score as important predictors.

1. This study pooled data from three clinical trials with heterogeneous designs. However, there is no evaluation or discussion on its effect on the results or conclusions.

2. The analysis was conducted with the “high-dose” versus “low-dose” tenapanor determined based on final dose at Week 8. However, the dose titration was determined based on serum phosphorus levels and tolerability. This may create circular inference.

3. In statistical analysis, it’s unclear what the model specification is exactly! Model specification should be clearly laid out in the section.

4. With current sample size in high-dose group, there is a concern for potential overfitting as it seems that there are 15 predictors in the multivariable model.

5. Dose itself is a time-varying treatment. Please comment on its implications or effect on the results and conclusions.

Reviewer #2: General assessment

This manuscript presents a pooled analysis of three clinical trials conducted in Japan to identify baseline patient characteristics associated with higher dose requirements of tenapanor in dialysis patients with hyperphosphatemia. The study addresses a clinically relevant and practical question, as dose titration of tenapanor is common in real-world practice yet predictors of higher dose requirements have not been well characterized.

Overall, the manuscript is technically sound, the data support the authors’ conclusions, and the statistical analyses are appropriate and adequately described. The study is presented in a clear and intelligible manner, and the findings provide novel insights that may help inform individualized dosing strategies in clinical practice.

Strengths

Clinical relevance: Identifying factors associated with higher tenapanor dose requirements is highly relevant for nephrologists managing hyperphosphatemia in dialysis patients.

Appropriate methodology: The pooled analysis is reasonable, and the use of both univariate and multivariate analyses to identify independent predictors is appropriate.

Clear results: The separation into low- and high-dose groups is well defined, and baseline comparisons are clearly presented.

Novel findings: The identification of serum TRACP-5b as a positive predictor and BSFS score as a negative predictor of higher dose requirement is novel and biologically plausible, linking bone turnover and bowel habits with tenapanor dose needs.

Balanced discussion: The authors appropriately acknowledge study limitations and the need for confirmation in larger, prospective real-world studies.

Minor comments / suggestions

The manuscript would benefit from a brief discussion clarifying the potential mechanistic link between elevated TRACP-5b levels and higher tenapanor dose requirements, particularly in relation to bone–mineral metabolism.

Conclusion and recommendation

In conclusion, this study is well conducted, methodologically appropriate, and presents clinically meaningful findings. The data adequately support the conclusions, and the manuscript meets the standards for publication. I recommend acceptance, with only minor editorial revisions if deemed necessary by the journal.

Reviewer #3: The paper addresses a practical clinical question — which dialysis patients need higher doses of tenapanor — using data pooled from three phase 3 trials. The two main findings (elevated TRACP-5b and lower BSFS scores predict higher dose requirements) are biologically plausible and modestly supported by the data, but some methodological concerns limit confidence in the conclusions as stated.

1. Study design — post-hoc retrospective stratification:

This is the most fundamental issue. Patients were assigned to "low-dose" or "high-dose" groups after 8 weeks of treatment based on where they ended up, not a prospectively defined protocol. This creates inherent confounding: dose escalation was driven by serum phosphorus levels per protocol, so patients with higher baseline phosphorus would mechanically receive higher doses. The high-dose group did indeed have higher baseline phosphorus (7.62 vs 7.24 mg/dL). The authors test phosphorus in the multivariate model but it drops to non-significance (p=0.098), which partly addresses this — but the circularity concern is not fully eliminated and should be discussed more explicitly.

2. The three trials differ substantially:

Trial A: HD patients, PB washout before enrollment, placebo-controlled

Trial B: HD patients, ongoing PB combination therapy, blinded phosphorus alerts driving dose changes

Trial C: PD patients (a different clinical population), open-label, 16 weeks

These differences in modality (HD vs PD), concurrent therapy (monotherapy vs combination), blinding, and dose-titration triggers mean the pooled sample is not homogeneous. The authors acknowledge this but dismiss separate analyses due to sample size. This is honest, but reviewers will press on whether pooling here is defensible.

3. Conflicts of interest:

Two authors (Tokunaga and Asada) are employees of Kyowa Kirin Co., Ltd., the funder. This is disclosed appropriately, but the fact that the sponsoring company's employees performed data curation and investigation is a potential source of bias that a peer reviewer is likely to flag.

**********

what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review?  For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

Dear Dr. Nagano,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR:  Please address the reviewers’ comments.

==============================

Please submit your revised manuscript by Aug 24 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Ken Iseri

Academic Editor

PLOS One

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: (No Response)

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

Reviewer #1: (No Response)

Reviewer #3: This pooled post-hoc analysis combines data from three Japanese phase 3 clinical trials (n=212) to identify which dialysis patients with hyperphosphatemia are most likely to need higher doses of tenapanor. Patients were retrospectively split into a low-dose group (5–10 mg/dose, n=127) and a high-dose group (20–30 mg/dose, n=85) based on their dose at Week 8, and baseline characteristics were compared using univariate and multivariate logistic regression. The analysis found that higher baseline levels of TRACP-5b and lower Bristol Stool Form Scale scores were independent predictors of needing a higher tenapanor dose. The authors conclude that patients with greater bone turnover or constipation-prone bowel habits are more likely to require dose escalation. They suggest that assessing bone turnover and bowel habits could help guide individualized dosing, while noting that larger, prospective real-world studies are needed to confirm these findings.

Minor issues: the discussion text still requires cleaning up — "Mechanistically, Approximately approximately 85% of total body phosphorus..." (line 350-351)

Table 3 footnote shows the low-dose group as n=133 while the efficacy tables use n=127 — worth double-checking this is intentional (safety set vs. efficacy/mITT set) and is clearly labeled as such, since it could read as an inconsistency to readers.

Pooling heterogeneous trial designs (HD washout/placebo-controlled vs. HD combination-therapy/blinded-alert-driven vs. PD/open-label/16-week) is addressed narratively but not statistically (no trial-stratified analysis or interaction term reported). Consider a sensitivity check showing the TRACP-5b/BSFS associations hold (even descriptively) within each trial (e.g., a forest plot by trial). If possible.

**********

what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review?  For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

Patient characteristics associated with the need for high doses of tenapanor hydrochloride in dialysis patients with hyperphosphatemia: A pooled analysis of three clinical trials

PONE-D-26-10484R2

Dear Dr. Nagano,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ken Iseri

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: