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Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis

  • Vincent M. BrandenburgEmail author
  • Smeeta Sinha
  • Jose-Vicente Torregrosa
  • Rekha Garg
  • Stephan Miller
  • Ana-Zeralda Canals
  • Daun Bahr
  • Pieter H. Joubert
  • Carolina Salcedo
  • Kevin J. Carroll
  • Alex Gold
  • Joan Perelló
Original Article

Abstract

Background

Calciphylaxis in end-stage renal disease is characterized by painful necrotic skin ulcers and high mortality. There are no approved therapies. SNF472, an intravenous formulation of myo-inositol hexaphosphate, inhibits the formation and growth of hydroxyapatite crystals, the final common pathway in the pathogenesis of vascular calcification.

Methods

In this open-label, single-arm study, calciphylaxis patients on thrice-weekly hemodialysis and standard care, received intravenous SNF472 3 times per week for 12 weeks. The primary endpoint was wound healing assessed using the quantitative Bates-Jensen Wound Assessment Tool (BWAT). Pain visual analog scale (VAS), quality of life (wound-QoL), and qualitative wound image review were secondary endpoints. Quantitative changes from baseline were analyzed by paired t-tests using multiple imputation to account for missing observations.

Results

Fourteen patients received SNF472. Improvements from baseline to week 12 were observed for mean BWAT score (− 8.1; P < 0.001), pain VAS (− 23.6 mm; P = 0.015) and wound-QoL global score (− 0.90; P = 0.003). Of the 9 patients with ulcerated lesions at baseline who completed treatment, wound image review showed improvement for 7. SNF472 was well tolerated with no serious treatment-related adverse events. The most common adverse events were infections which occur frequently in patients on hemodialysis. None of these were considered as treatment-related.

Conclusions

SNF472 was well-tolerated and improvements from baseline to week 12 in wound healing, pain, and quality of life were observed. A randomized, double-blind, placebo-controlled trial is planned to evaluate SNF472 in patients with calciphylaxis.

Keywords

SNF472 Calciphylaxis Dialysis myo-inositol hexaphosphate CUA 

Notes

Acknowledgements

The study was supported by Laboratoris Sanifit. Medical writing support from Jonathan Latham of PharmaScribe, LLC was funded by Sanifit. The study was conducted in the US at Frenova Renal Research® and Davita Kidney Care sites, and in the UK at the Salford Royal NHS Foundation Trust. Sanifit thanks Dr. Barbara Bates-Jensen for permission to use the BWAT in this study.

Author contributions

VB, SS, JT, AZC, PJ, CS, and JP contributed to the study concept and design. VB and SS contributed to the acquisition of data. VB, SS, RG, SM, AZC, CS, KJC, AG, and JP contributed to the conduct, analysis and interpretation of the data. SM and RG drafted the article. All authors contributed to critical editing and revising the article for important intellectual content. All authors provided final approval of the version to be published. All authors agree to be accountable for all aspects of the work.

Compliance with ethical standards

Conflict of interest

VB is a consultant to Pharmacosmos, Vifor, and FMC, received lecture fees from Amgen, Pfizer, Bayer, Pharmacosmos, Vifor, FMC, Servier, Novartis, Daiichi-Sankyo, and Cardiobridge, received a grant for the European Calciphylaxis Network EuCalNet from Amgen, and received grants from Pfizer, Bayer, Sanifit, Pharmacosmos, Vifor, FMC, Servier, Novartis, Daiichi-Sankyo, and Cardiobridge. SS is a consultant to Sanifit, and received lecture fees from Vifor Fresenius, MSD, and Boehringer Ingelheim. JT has no conflicts to disclose. KJC and PJ, are consultants to Sanifit. RG, SM and AG are employees and shareholders of Sanifit Therapeutics. AZC is an employee and shareholders of Sanifit and has a patent pending related to SNF472. CS is an employee of Sanifit and has patents related to SNF472. JP is an employee and shareholder of Sanifit, and has patents owned or controlled by Sanifit.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Patients gave written informed consent to participate.

Supplementary material

40620_2019_631_MOESM1_ESM.docx (581 kb)
Supplementary material 1 (DOCX 579 kb)

References

  1. 1.
    Goel SK, Bellovich K, McCullough PA (2011) Treatment of severe metastatic calcification and calciphylaxis in dialysis patients. Int J Nephrol 2011:701603.  https://doi.org/10.4061/2011/701603 CrossRefGoogle Scholar
  2. 2.
    Nunley JR (2017) Calciphylaxis. https://emedicine.medscape.com/article/1095481-overview. Accessed 1 June 2019
  3. 3.
    Schlieper G, Brandenburg V, Ketteler M, Floege J (2009) Sodium thiosulfate in the treatment of calcific uremic arteriolopathy. Nat Rev Nephrol 5:539–543.  https://doi.org/10.1038/nrneph.2009.99 CrossRefGoogle Scholar
  4. 4.
    Oliveira TM, Frazao JM (2015) Calciphylaxis: from the disease to the diseased. J Nephrol 28:531–540.  https://doi.org/10.1007/s40620-015-0192-2 CrossRefGoogle Scholar
  5. 5.
    Angelis M, Wong LL, Myers SA, Wong LM (1997) Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery 122:1083–1089.  https://doi.org/10.1016/S0039-6060(97)90212-9 (discussion 1089–1090) CrossRefGoogle Scholar
  6. 6.
    Budisavljevic MN, Cheek D, Ploth DW (1996) Calciphylaxis in chronic renal failure. J Am Soc Nephrol 7:978–982Google Scholar
  7. 7.
    Nigwekar SU, Thadhani R, Brandenburg VM (2018) Calciphylaxis. N Engl J Med 378:1704–1714.  https://doi.org/10.1056/NEJMra1505292 CrossRefGoogle Scholar
  8. 8.
    Brandenburg VM, Kramann R, Rothe H, Kaesler N, Korbiel J, Specht P, Schmitz S, Krüger T, Floege J, Ketteler M (2017) Calcific uraemic arteriolopathy (calciphylaxis): data from a large nationwide registry. Nephrol Dial Transplant 32:126–132.  https://doi.org/10.1093/ndt/gfv438 Google Scholar
  9. 9.
    Sanguankeo A, Thamcharoen N, Upala S (2017) Calciphylaxis in a nondialysis patient treated with sodium thiosulfate and high dose of oxygen. Clin Nephrol Case Stud 5:38–41Google Scholar
  10. 10.
    Mochel MC, Arakaki RY, Wang G, Kroshinsky D, Hoang MP (2013) Cutaneous calciphylaxis: a retrospective histopathologic evaluation. Am J Dermatopathol 35:582–586.  https://doi.org/10.1097/DAD.0b013e31827c7f5d CrossRefGoogle Scholar
  11. 11.
    Nigwekar SU, Kroshinsky D, Nazarian RM, Goverman J, Malhotra R, Jackson VA, Kamdar MM, Steele DJ, Thadhani RI (2015) Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis 66:133–146.  https://doi.org/10.1053/j.ajkd.2015.01.034 CrossRefGoogle Scholar
  12. 12.
    Hafner J, Keusch G, Wahl C, Sauter B, Hurlimann A, von Weizsacker F, Krayenbuhl M, Biedermann K, Brunner U, Helfenstein U (1995) Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 33:954–962CrossRefGoogle Scholar
  13. 13.
    Fine A, Zacharias J (2002) Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int 61:2210–2217.  https://doi.org/10.1046/j.1523-1755.2002.00375.x CrossRefGoogle Scholar
  14. 14.
    Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR (2007) Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol 56:569–579.  https://doi.org/10.1016/j.jaad.2006.08.065 CrossRefGoogle Scholar
  15. 15.
    Auriemma M, Carbone A, Di Liberato L, Cupaiolo A, Caponio C, De Simone C, Tulli A, Bonomini M, Amerio P (2011) Treatment of cutaneous calciphylaxis with sodium thiosulfate: two case reports and a review of the literature. Am J Clin Dermatol 12:339–346.  https://doi.org/10.2165/11587060-000000000-00000 CrossRefGoogle Scholar
  16. 16.
    Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr (2013) Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol 8:1162–1170.  https://doi.org/10.2215/CJN.09880912 CrossRefGoogle Scholar
  17. 17.
    Peng T, Zhuo L, Wang Y, Jun M, Li G, Wang L, Hong D (2018) Systematic review of sodium thiosulfate in treating calciphylaxis in chronic kidney disease patients. Nephrology (Carlton) 23:669–675.  https://doi.org/10.1111/nep.13081 CrossRefGoogle Scholar
  18. 18.
    Ferrer MD, Ketteler M, Tur F, Tur E, Isern B, Salcedo C, Joubert PH, Behets GJ, Neven E, D’Haese PC, Perello J (2018) Characterization of SNF472 pharmacokinetics and efficacy in uremic and non-uremic rats models of cardiovascular calcification. PLoS ONE 13:e0197061.  https://doi.org/10.1371/journal.pone.0197061 CrossRefGoogle Scholar
  19. 19.
    Ferrer MD, Perez MM, Canaves MM, Buades JM, Salcedo C, Perello J (2017) A novel pharmacodynamic assay to evaluate the effects of crystallization inhibitors on calcium phosphate crystallization in human plasma. Sci Rep 7:6858.  https://doi.org/10.1038/s41598-017-07203-x CrossRefGoogle Scholar
  20. 20.
    Perelló J, Gómez M, Ferrer MD, Rodríguez NY, Salcedo C, Buades JM, Pérez MM, Torregrosa JV, Martín E, Maduell F (2018) SNF472, a novel inhibitor of vascular calcification, could be administered during hemodialysis to attain potentially therapeutic phytate levels. J Nephrol 31:287–296.  https://doi.org/10.1007/s40620-018-0471-9 CrossRefGoogle Scholar
  21. 21.
    Perelló J, Joubert PH, Ferrer MD, Canals AZ, Sinha S, Salcedo C (2018) First-time-in-human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification. Br J Clin Pharmacol 84:2867–2876.  https://doi.org/10.1111/bcp.13752 CrossRefGoogle Scholar
  22. 22.
    Bates-Jensen BM, Vredevoe DL, Brecht ML (1992) Validity and reliability of the pressure sore status tool. Decubitus 5:20–28Google Scholar
  23. 23.
    Augustin M, Baade K, Heyer K, Price PE, Herberger K, Wild T, Engelhardt M, Debus ES (2017) Quality-of-life evaluation in chronic wounds: comparative analysis of three disease-specific questionnaires. Int Wound J 14:1299–1304.  https://doi.org/10.1111/iwj.12803 CrossRefGoogle Scholar
  24. 24.
    Olsen MF, Bjerre E, Hansen MD, Tendal B, Hilden J, Hróbjartsson A (2018) Minimum clinically important differences in chronic pain vary considerably by baseline pain and methodological factors: systematic review of empirical studies. J Clin Epidemiol 101:87–106.e2.  https://doi.org/10.1016/j.jclinepi.2018.05.007 CrossRefGoogle Scholar
  25. 25.
    Olsen MF, Bjerre E, Hansen MD, Hilden J, Landler NE, Tendal B, Hróbjartsson A (2017) Pain relief that matters to patients: systematic review of empirical studies assessing the minimum clinically important difference in acute pain. BMC Med 15:35.  https://doi.org/10.1186/s12916-016-0775-3 CrossRefGoogle Scholar
  26. 26.
    Torregrosa JV, Ramos AM (2010) Use of bisphosphonates in chronic kidney disease. Nefrologia 30:288–296Google Scholar
  27. 27.
    Torregrosa JV, Duran CE, Barros X, Blasco M, Arias M, Cases A, Campistol JM (2012) Successful treatment of calcific uraemic arteriolopathy with bisphosphonates. Nefrologia 32:329–334Google Scholar
  28. 28.
    Jeong HS, Dominguez AR (2016) Calciphylaxis: controversies in pathogenesis, diagnosis and treatment. Am J Med Sci 351:217–227.  https://doi.org/10.1016/j.amjms.2015.11.015 CrossRefGoogle Scholar
  29. 29.
    Riemer CA, El-Azhary RA, Wu KL, Strand JJ, Lehman JS (2017) Underreported use of palliative care and patient-reported outcome measures to address reduced quality of life in patients with calciphylaxis: a systematic review. Br J Dermatol 177:1510–1518.  https://doi.org/10.1111/bjd.15702 CrossRefGoogle Scholar
  30. 30.
    Hayden MR, Goldsmith DJ (2010) Sodium thiosulfate: new hope for the treatment of calciphylaxis. Semin Dial 23:258–262.  https://doi.org/10.1111/j.1525-139X.2010.00738.x CrossRefGoogle Scholar
  31. 31.
    Yu Z, Gu L, Pang H, Fang Y, Yan H, Fang W (2015) Sodium thiosulfate: an emerging treatment for calciphylaxis in dialysis patients. Case Rep Nephrol Dial 5:77–82.  https://doi.org/10.1159/000380945 CrossRefGoogle Scholar
  32. 32.
    Floege J, Kubo Y, Floege A, Chertow GM, Parfrey PS (2015) The effect of cinacalcet on calcific uremic arteriolopathy events in patients receiving hemodialysis: the EVOLVE trial. Clin J Am Soc Nephrol 10:800–807.  https://doi.org/10.2215/CJN.10221014 CrossRefGoogle Scholar
  33. 33.
    Russo D, Capuano A, Cozzolino M, Napolitano P, Mosella F, Russo L, Saviano C, Zoccali C (2016) Multimodal treatment of calcific uraemic arteriolopathy (calciphylaxis): a case series. Clin Kidney J 9:108–112.  https://doi.org/10.1093/ckj/sfv120 CrossRefGoogle Scholar

Copyright information

© Italian Society of Nephrology 2019

Authors and Affiliations

  • Vincent M. Brandenburg
    • 1
    Email author
  • Smeeta Sinha
    • 2
    • 3
  • Jose-Vicente Torregrosa
    • 4
  • Rekha Garg
    • 5
  • Stephan Miller
    • 5
  • Ana-Zeralda Canals
    • 6
  • Daun Bahr
    • 5
  • Pieter H. Joubert
    • 7
  • Carolina Salcedo
    • 6
  • Kevin J. Carroll
    • 8
  • Alex Gold
    • 5
  • Joan Perelló
    • 6
    • 9
  1. 1.Department of Cardiology, Nephrology, and Intensive Care MedicineRhein-Maas KlinikumWürselenGermany
  2. 2.Salford Royal NHS Foundation TrustSalfordUK
  3. 3.University of ManchesterManchesterUK
  4. 4.Nephrology DepartmentHospital ClinicBarcelonaSpain
  5. 5.Sanifit TherapeuticsSan DiegoUSA
  6. 6.Sanifit TherapeuticsPalmaSpain
  7. 7.King’s CollegeLondonUK
  8. 8.KJC StatisticsCheshireUK
  9. 9.University of the Balearic IslandsPalmaSpain

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