Hexasodium fytate for the treatment of calciphylaxis: a randomised, double-blind, phase 3, placebo-controlled trial with an open-label extension

Smeeta Sinha^{1

2}, Sagar U Nigwekar^{3

4}, Vincent Brandenburg⁵, Lisa J Gould⁶, Thomas E Serena⁷, Sharon M Moe⁸, George R Aronoff⁹, Dinesh K Chatoth¹⁰, Jeffrey L Hymes¹¹, Kevin J Carroll¹², Gabriela Alperovich¹³, Laurence H Keller¹⁴, Joan Perelló^{15

16}, Alex Gold^{17

18}, Glenn M Chertow¹⁸

Affiliations

¹ Renal Medicine, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK.
² Faculty of Biology, Medicine, and Health, University of Manchester, UK.
³ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Harvard Medical School, Boston, MA, USA.
⁵ Cardiology and Nephrology, Rhein-Maas Hospital, Würselen, Germany.
⁶ South Shore Health Department of Surgery, South Shore Health Center for Wound Healing, Weymouth, MA, USA.
⁷ SerenaGroup Research Foundation, Cambridge, MA, USA.
⁸ Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁹ Vice President, Clinical Affairs, DaVita Kidney Care, Denver, CO, USA.
¹⁰ Associate Chief Medical Officer, Fresenius Kidney Care, Waltham, MA, USA.
¹¹ Executive Vice President, Global Head of Clinical Affairs, Chief Medical Officer, Care Delivery, Fresenius Medical Care, Waltham, MA, USA.
¹² KJC Statistics Ireland Limited, Dublin, Ireland.
¹³ Clinical Development, CSL Vifor, Madrid, Spain.
¹⁴ Clinical Development Consultant, Ann Arbor, MI, USA.
¹⁵ Research and Development, CSL Vifor, Palma de Mallorca, Spain.
¹⁶ University Institute of Health Sciences Research (IUNICS- IDISBA), University of the Balearic Islands, Palma de Mallorca, Spain.
¹⁷ Clinical Development Consultant, Incline Village, NV, USA.
¹⁸ Medicine, Stanford University School of Medicine, Stanford, CA, USA.

PMID: 39252867
PMCID: PMC11381625
DOI: 10.1016/j.eclinm.2024.102784

Hexasodium fytate for the treatment of calciphylaxis: a randomised, double-blind, phase 3, placebo-controlled trial with an open-label extension

Smeeta Sinha et al. EClinicalMedicine. 2024.

. 2024 Aug 16:75:102784.

doi: 10.1016/j.eclinm.2024.102784. eCollection 2024 Sep.

Authors

Affiliations

¹ Renal Medicine, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK.
² Faculty of Biology, Medicine, and Health, University of Manchester, UK.
³ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Harvard Medical School, Boston, MA, USA.
⁵ Cardiology and Nephrology, Rhein-Maas Hospital, Würselen, Germany.
⁶ South Shore Health Department of Surgery, South Shore Health Center for Wound Healing, Weymouth, MA, USA.
⁷ SerenaGroup Research Foundation, Cambridge, MA, USA.
⁸ Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁹ Vice President, Clinical Affairs, DaVita Kidney Care, Denver, CO, USA.
¹⁰ Associate Chief Medical Officer, Fresenius Kidney Care, Waltham, MA, USA.
¹¹ Executive Vice President, Global Head of Clinical Affairs, Chief Medical Officer, Care Delivery, Fresenius Medical Care, Waltham, MA, USA.
¹² KJC Statistics Ireland Limited, Dublin, Ireland.
¹³ Clinical Development, CSL Vifor, Madrid, Spain.
¹⁴ Clinical Development Consultant, Ann Arbor, MI, USA.
¹⁵ Research and Development, CSL Vifor, Palma de Mallorca, Spain.
¹⁶ University Institute of Health Sciences Research (IUNICS- IDISBA), University of the Balearic Islands, Palma de Mallorca, Spain.
¹⁷ Clinical Development Consultant, Incline Village, NV, USA.
¹⁸ Medicine, Stanford University School of Medicine, Stanford, CA, USA.

PMID: 39252867
PMCID: PMC11381625
DOI: 10.1016/j.eclinm.2024.102784

Abstract

Background: In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions.

Methods: In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7 mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906.

Findings: Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)], -5.3 [5.2] versus -6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI): -2.5, 3.0]; p = 0.88) and Pain VAS (mean [SD], -19.5 [26.9] versus -32.2 [38.5]; least squares mean difference, 11.5 [96% CI: -4.8, 27.8]; p = 0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group.

Interpretation: In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group.

Funding: Funded by Sanifit, a CSL Vifor company.

Keywords: Calcific uraemic arteriolopathy; Calcification; Calciphylaxis; Dialysis; Hexasodium fytate; SNF472.

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Conflict of interest statement

SS received consulting fees from Sanifit and Inozyme Pharma Inc; honoraria from AstraZeneca, Bayer, Sanofi-Genzyme, Novartis, CSL Vifor, GSK, Menarini, Medscape, and Boehringer-Ingelheim; support for attending meetings and/or travel from Sanifit, AstraZeneca, Novartis, and CSL Vifor. SUN received research funding to institution from Laboratoris Sanifit, CSL/Vifor, Hope Pharma, Inozyme Pharma, Epizon; consulting fees from Laboratoris Sanifit, CSL/Vifor, Inozyme Pharma, and Epizon; medical writing support from Laboratoris Sanifit and CSL/Vifor; royalties from UpToDate; and support for attending meetings and/or travel from Inozyme Pharma. LJG received consulting fees from Sanifit Therapeutics. SMM received consulting fees from Ardelyx, Sanfit, and Inozyme; and holds stock or stock options in Eli Lilly. DKC is an employee of Fresenius Medical Care and declares spousal stock in Amgen. KJC received consulting fees from Sanifit srl and Vifor Pharma. GA is an employee of CSL Vifor. LHK was an employee of and received stock compensation from CSL Vifor during the study. JP received consulting fees and stocks or stock options from Sanifit Therapeutics, which owns or has rights on patents related to this work where JP is a coinventor. AG was an employee of Sanifit Therapeutics and CSL Vifor and received consulting fees from Sanifit Therapeutics and CSL Vifor. GMC received graphics support (no writing support) from Sanifit, Vifor, and CSL Behring; received consulting fees from Sanifit, Akebia, AstraZeneca, CSL Behring, and Vertex; participated on a data safety monitoring board or Advisory Board for Ardelyx, Calico, and Miromatrix; served in a leadership or fiduciary role for Satellite Healthcare; received stock or stock options from CloudCath, Duract, Eliaz Therapeutics Outset, Renibus, and Unicycive. All other authors declare no competing interests.

Figures

**Fig. 1**
**Enrolment and disposition of study participants**. ITT, intention-to-treat analysis set; mITT, modified intention-to-treat analysis set. †One subject randomised to the placebo group received hexasodium fytate during Week 11 and Week 12 in Part 1. The subject was included in the placebo group of the ITT and mITT populations for efficacy analyses and in the hexasodium fytate group of the Safety Analysis Population for safety analyses. ‡Other reasons for discontinuation of treatment in Part 2: hexasodium fytate, expired study drug (1 patient); placebo, unable to administer study drug, ampule broken, and scheduling issues (1 patient each).

**Fig. 2**
**Primary efficacy outcomes**. BWAT, Bates-Jensen Wound Assessment Tool; CUA, calcific uraemic arteriolopathy (calciphylaxis); LS, least squares; SE, standard error and VAS, visual analogue scale. ∗Shown are results in the modified intention-to-treat population for alternate primary outcomes of mean ± SE change from baseline to Week 12 in BWAT-CUA score (Panel A) and mean ± SE change from baseline to Week 12 in Pain VAS Score (Panel B).

**Fig. 3**
**Treatment discontinuation, death, calciphylaxis-related events, and hospitalisation**. CI, confidence interval; CUA, calcific uraemic arteriolopathy (calciphylaxis); ITT, intention-to-treat. Panels A and B show treatment discontinuation rates by treatment group in the Safety Analysis Population for Part 1 (A) and Part 2 (B). Panels C and D show the incidences of death, calciphylaxis-related events (for each adverse event, the investigator reported whether the event was related to calciphylaxis) leading to hospitalisation, and calciphylaxis-related events not leading to hospitalisation in the Safety Analysis Population through Week 12 cumulative (C) and through end of study (D). Panels E and F show Kaplan–Meier analyses of the composite of death or calciphylaxis-related hospitalisation (E) and death (F) in the ITT population. Panel G shows days alive and out of hospital weighted for exposure, by patient, through Week 12 and through end of study in the ITT Population.

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References

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1. Nigwekar S.U., Zhao S., Wenger J., et al. A nationally representative study of calcific uremic arteriolopathy risk factors. J Am Soc Nephrol. 2016;27:3421–3429. - PMC - PubMed
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Hexasodium fytate for the treatment of calciphylaxis: a randomised, double-blind, phase 3, placebo-controlled trial with an open-label extension

Affiliations

Hexasodium fytate for the treatment of calciphylaxis: a randomised, double-blind, phase 3, placebo-controlled trial with an open-label extension

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

LinkOut - more resources

Full Text Sources