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Original research
Treatment switch in Fabry disease- a matter of dose?
  1. Malte Lenders1,
  2. Peter Nordbeck2,
  3. Sima Canaan-Kühl3,
  4. Lukas Kreul2,
  5. Thomas Duning4,
  6. Lora Lorenz2,
  7. Christian Pogoda5,
  8. Stefan-Martin Brand6,
  9. Christoph Wanner2,
  10. Eva Brand1
  1. 1Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology and Interdisciplinary Fabry Center Münster (IFAZ), University Hospital Münster, Münster, Germany
  2. 2Department of Internal Medicine I, Divisions of Cardiology and Nephrology, Comprehensive Heart Failure Center, Fabry Center for Interdisciplinary Therapy (FAZIT), University Hospital and University of Würzburg, Würzburg, Germany
  3. 3Department of Medicine, Division of Nephrology, Charité, Universitätsmedizin Campus Mitte, Berlin, Germany
  4. 4Department of Neurology, and Interdisciplinary Fabry Center Münster (IFAZ), University Hospital Münster, Münster, Germany
  5. 5Department of Cardiology I – Coronary and Peripheral Vascular Disease, Heart Failure, and Interdisciplinary Fabry Center Münster (IFAZ), University Hospital Münster, Münster, Germany
  6. 6Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, and Interdisciplinary Fabry Center Münster (IFAZ), University Hospital Münster, Münster, Germany
  1. Correspondence to Professor Eva Brand, Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology and Interdisciplinary Fabry Center Münster (IFAZ), University Hospital Münster, Münster, Germany; Eva.Brand{at}ukmuenster.de

Abstract

Background Patients with Fabry disease (FD) on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in chronic kidney disease epidemiology collaboration-based estimated glomerular filtration rate (eGFR) and a worsened plasma lyso-Gb3 decrease. Hence, the most effective dose is still a matter of debate.

Methods In this prospective observational study, we assessed end-organ damage and clinical symptoms in 78 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, which were assigned to continue this treatment (agalsidase-beta, regular-dose group, n=17); received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n=22); or were re-switched to agalsidase-beta after receiving agalsidase-alfa for 12 months (re-switch group, n=39) with a follow-up of 88±25 months.

Results No differences for clinical events were observed for all groups. Patients within the re-switch group started with the worst eGFR values at baseline (p=0.0217). Overall, eGFR values remained stable in the regular-dose group (p=0.1052) and decreased significantly in the re-switch and switch groups (p<0.0001 and p=0.0052, respectively). However, in all groups males presented with an annual loss of eGFR by –2.9, –2.5 and −3.9 mL/min/1.73 m² (regular-dose, re-switch, switch groups, all p<0.05). In females, eGFR decreased significantly only in the re-switch group by −2.9 mL/min/1.73 m² per year (p<0.01). Lyso-Gb3 decreased in the re-switch group after a change back to agalsidase-beta (p<0.05).

Conclusions Our data suggest that a re-switch to high dosage of agalsidase results in a better biochemical response, but not in a significant renal amelioration especially in classical males.

  • genetics
  • renal medicine
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Footnotes

  • Contributors Research idea and study design: all authors; data acquisition: ML, SC-K, PN, LL, LK, TD, SR, CP, CW, EB; data analysis/interpretation: all authors; statistical analysis: ML; manuscript writing: ML, EB. Each author contributed important intellectual content during manuscript drafting and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. EB takes responsibility that this study has been reported honestly, accurately and transparently; that no important aspects of the study have been omitted and that any discrepancies from the study as planned have been explained.

  • Funding This study was funded by Genzyme Europe. The researchers were independent of the funding agency. Grants were used for research meetings and support in collection of the data.

  • Competing interests ML and TD received speaker honoraria from Amicus Theraputics, Sanofi Genzyme and Shire/Takeda. S-MB has received speaker honoraria from Shire/Takeda. CW, SC-K and EB received speaker and advisory board honoraria from Amicus Therapeutics, Greenovation, Sanofi Genzyme and Shire/Takeda. PN received speaker and advisory board honoraria from Amicus Therapeutics, Greenovation, Idorsia, Sanofi Genzyme and Shire/Takeda. CW is a member of the Fabry Registry European Board of Advisors and received travel assistance and speaker honoraria. Research grants were given to the institutions (Würzburg and Münster) by Amicus Therapeutics, Sanofi Genzyme and Shire/Takeda.

  • Patient consent for publication Not required.

  • Ethics approval All investigations were performed after approval of the Medical Association of Westfalian-Lippe and the Ethical Committee of the Medical Faculty of the University of Muenster and the ethics committees of the participating centres (project-nos.: 2011–347 f, date of report: 7 July 2011).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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